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Buck 2017 PLOS ONE + (Alterations in mitochondrial respiration a … Alterations in mitochondrial respiration are an important hallmark of Huntington's disease (HD), one of the most common monogenetic causes of neurodegeneration. The ubiquitous expression of the disease causing mutant huntingtin gene raises the prospect that mitochondrial respiratory deficits can be detected in skeletal muscle. While this tissue is readily accessible in humans, transgenic animal models offer the opportunity to cross-validate findings and allow for comparisons across organs, including the brain. The integrated respiratory chain function of the human ''vastus lateralis'' muscle was measured by high-resolution respirometry (HRR) in freshly taken fine-needle biopsies from seven pre-manifest HD expansion mutation carriers and nine controls. The respiratory parameters were unaffected. For comparison skeletal muscle isolated from HD knock-in mice (HdhQ111) as well as a broader spectrum of tissues including cortex, liver and heart muscle were examined by HRR. Significant changes of mitochondrial respiration in the HdhQ knock-in mouse model were restricted to the liver and the cortex. Mitochondrial mass as quantified by mitochondrial DNA copy number and citrate synthase activity was stable in murine HD-model tissue compared to control. mRNA levels of key enzymes were determined to characterize mitochondrial metabolic pathways in HdhQ mice. We demonstrated the feasibility to perform high-resolution respirometry measurements from small human HD muscle biopsies. Furthermore, we conclude that alterations in respiratory parameters of pre-manifest human muscle biopsies are rather limited and mirrored by a similar absence of marked alterations in HdhQ skeletal muscle. In contrast, the HdhQ111 murine cortex and liver did show respiratory alterations highlighting the tissue specific nature of mutant huntingtin effects on respiration. mutant huntingtin effects on respiration.)
Ekbal 2013 Chest + (Alterations in oxygen transport and use ar … Alterations in oxygen transport and use are integral to the development of multiple organ failure; therefore, the ultimate goal of resuscitation is to restore effective tissue oxygenation and cellular metabolism. Hemodynamic monitoring is the cornerstone of management to promptly identify and appropriately manage (impending) organ dysfunction. Prospective randomized trials have confirmed outcome benefit when preemptive or early treatment is directed toward maintaining or restoring adequate tissue perfusion. However, treatment end points remain controversial, in large part because of current difficulties in determining what constitutes "optimal." Information gained from global whole-body monitoring may not detect regional organ perfusion abnormalities until they are well advanced. Conversely, the ideal "canary" organ that is readily accessible for monitoring, yet offers an early and sensitive indicator of tissue "unwellness," remains to be firmly identified. This review describes techniques available for real-time monitoring of tissue perfusion and metabolism and highlights novel developments that may complement or even supersede current tools.omplement or even supersede current tools.)
Schaefer 2017 Neurophotonics + (Alterations of cellular bioenergetics are … Alterations of cellular bioenergetics are a common feature in most neurodegenerative disorders. However, there is a selective vulnerability of different brain regions, cell types, and even mitochondrial populations to these metabolic disturbances. Thus, the aim of our study was to establish and validate an ''in vivo'' metabolic imaging technique to screen for mitochondrial function on the subcellular level. Based on nicotinamide adenine dinucleotide (phosphate) fluorescence lifetime imaging microscopy [NAD(P)H FLIM], we performed a quantitative correlation to high-resolution respirometry. Thereby, we revealed mitochondrial matrix pH as a decisive factor in imaging NAD(P)H redox state. By combining both parameters, we illustrate a quantitative, high-resolution assessment of mitochondrial function in metabolically modified cells as well as in an amyloid precursor protein-overexpressing model of Alzheimer's disease. Our metabolic imaging technique provides the basis for dissecting mitochondrial deficits not only in a range of neurodegenerative diseases, shedding light onto bioenergetic failures of cells remaining in their metabolic microenvironment.ining in their metabolic microenvironment.)
Koliaki 2013 Mol Cell Endocrinol + (Alterations of hepatic mitochondrial funct … Alterations of hepatic mitochondrial function have been observed in states of insulin resistance and non-alcoholic fatty liver disease (NAFLD). Patients with overt type 2 diabetes mellitus (T2DM) can exhibit reduction in hepatic adenosine triphosphate (ATP) synthesis and impaired repletion of their hepatic ATP stores upon ATP depletion by fructose. Obesity and NAFLD may also associate with impaired ATP recovery after ATP-depleting challenges and augmented oxidative stress in the liver. On the other hand, patients with obesity or NAFLD can present with upregulated hepatic anaplerotic and oxidative fluxes, including β-oxidation and tricarboxylic cycle activity. The present review focuses on the methods and data on hepatic energy metabolism in various states of human insulin resistance. We propose that the liver can adapt to increased lipid exposition by greater lipid storing and oxidative capacity, resulting in increased oxidative stress, which in turn could deteriorate hepatic mitochondrial function in chronic insulin resistance and NAFLD.n in chronic insulin resistance and NAFLD.)
Fazzini 2016 Abstract Mito Xmas Meeting Innsbruck + (Alterations of mitochondrial DNA (mtDNA) c … Alterations of mitochondrial DNA (mtDNA) copy number appear to be associated with several pathologies including encephalopathies and neuropathies as well as the process of aging [1-2].The aim of this study was to set up a reliable quantitative PCR based assay for mitochondrial DNA copy number determination meeting quality requirements for mtDNA specificity.We established a duplex quantitative PCR assay that allows for targeting a single copy nuclear gene (ß2-microglobulin) and the mtDNA (t-RNA Leu) simultaneously. The use of a plasmid containing both targets in a 1:1 ratio was used to normalize against differences in emission intensities of the fluorescent dyes VIC and FAM. QPCR on the serial dilution of the calibrator plasmid revealed that the FAM dye emission signal exceeded the VIC signal, resulting in a ΔCT value of up to 1.2 cycles corresponding to more than a double amount of molecules. Using the plasmid calibrator with internal positive controls reduced the intra-assay variability from 21% (uncorrected) to 7% (plasmid corrected). We evaluated the applicability of the method by using DNA samples that were isolated with different methods and revealed significantly different numbers of mtDNA copies (copy number ratio: salting out/magnetic beads = 1.65).We developed a sensitive and robust assay for mitochondrial copy number detection relative to nuclear DNA. The use of the dual insert calibrator plasmid allows for correction against unequal emission intensities of the differently fluorescence labelled targets. Furthermore, we discovered that the diverse extraction methods selectively isolate different DNA molecules within a sample.e different DNA molecules within a sample.)
Pak 2013 Am J Respir Cell Mol Biol + (Alterations of mitochondrial membrane pote … Alterations of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitochondrial respiration are possible triggers of pulmonary vascular remodeling in pulmonary hypertension (PH). We investigated the role of MMP in PH and hypothesized that deletion of the mitochondrial uncoupling protein 2 (UCP2) increases MMP, thus promoting pulmonary vascular remodeling and PH. MMP was measured by JC-1 in isolated pulmonary arterial smooth muscle cells (PASMCs) of patients with PH and animals with PH induced by exposure to monocrotaline (MCT) or chronic hypoxia. PH was quantified ''in vivo'' in UCP2-deficient (UCP2(-/-)) mice by hemodynamics, morphometry, and echocardiography. ROS were measured by electron spin resonance spectroscopy and proliferation by thymidine incorporation. Mitochondrial respiration was investigated by high-resolution respirometry. MMP was increased in PASMCs of patients and in animal models of PH. UCP2(-/-) mice exhibited pulmonary vascular remodeling and mild PH compared with wild-type (WT) mice. PASMCs of UCP2(-/-) mice showed increased proliferation, MMP, and ROS release. Increased proliferation of UCP2(-/-) PASMCs could be attenuated by ROS inhibitors and inhibited by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, which decreased MMP to the level of WT mice. Mitochondrial respiration was altered in PASMCs from MCT rats and PASMCs exposed to hypoxia but not in isolated pulmonary mitochondria of UCP2(-/-) mice or PASMCs after treatment with small interfering RNA for UCP2. Our data suggest that increased MMP causes vascular remodeling in UCP2(-/-) mice partially via increased ROS. In chronic hypoxia and MCT-induced PH, additional pathomechanisms such as decreased respiration may play a role. as decreased respiration may play a role.)
Goldberg 2019 Biochem J + (Alterations to branched-chain keto acid (B … Alterations to branched-chain keto acid (BCKA) oxidation have been implicated in a wide variety of human diseases, ranging from diabetes to cancer. Although global shifts in BCKA metabolism-evident by gene transcription, metabolite profiling, and ''in vivo'' flux analyses have been documented across various pathological conditions, the underlying biochemical mechanism(s) within the mitochondrion remain largely unknown. ''In vitro'' experiments using isolated mitochondria represent a powerful biochemical tool for elucidating the role of the mitochondrion in driving disease. Such analyses have routinely been utilized across disciplines to shed valuable insight into mitochondrial-linked pathologies. That said, few studies have attempted to model ''in vitro'' BCKA oxidation in isolated organelles. The impetus for the present study stemmed from the knowledge that complete oxidation of each of the three BCKAs involves a reaction dependent upon bicarbonate and ATP, both of which are not typically included in respiration experiments. Based on this, it was hypothesized that the inclusion of exogenous bicarbonate and stimulation of respiration using physiological shifts in ATP-free energy, rather than excess ADP, would allow for maximal BCKA-supported respiratory flux in isolated mitochondria. This hypothesis was confirmed in mitochondria from several mouse tissues, including heart, liver and skeletal muscle. What follows is a thorough characterization and validation of a novel biochemical tool for investigating BCKA metabolism in isolated mitochondria.© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.ed on behalf of the Biochemical Society.)
Goldberg 2021 Biochem J + (Alterations to branched-chain keto acid (B … Alterations to branched-chain keto acid (BCKA) oxidation have been implicated in a wide variety of human diseases, ranging from diabetes to cancer. Although global shifts in BCKA metabolism-evident by gene transcription, metabolite profiling, and ''in vivo'' flux analyses have been documented across various pathological conditions, the underlying biochemical mechanism(s) within the mitochondrion remain largely unknown. ''In vitro'' experiments using isolated mitochondria represent a powerful biochemical tool for elucidating the role of the mitochondrion in driving disease. Such analyses have routinely been utilized across disciplines to shed valuable insight into mitochondrial-linked pathologies. That said, few studies have attempted to model ''in vitro'' BCKA oxidation in isolated organelles. The impetus for the present study stemmed from the knowledge that complete oxidation of each of the three BCKAs involves a reaction dependent upon bicarbonate and ATP, both of which are not typically included in respiration experiments. Based on this, it was hypothesized that the inclusion of exogenous bicarbonate and stimulation of respiration using physiological shifts in ATP-free energy, rather than excess ADP, would allow for maximal BCKA-supported respiratory flux in isolated mitochondria. This hypothesis was confirmed in mitochondria from several mouse tissues, including heart, liver and skeletal muscle. What follows is a thorough characterization and validation of a novel biochemical tool for investigating BCKA metabolism in isolated mitochondria. BCKA metabolism in isolated mitochondria.)
Fisar 2019 Clin Biochem + (Altered amyloid metabolism and mitochondri … Altered amyloid metabolism and mitochondrial dysfunction play key roles in the development of Alzheimer's disease (AD). We asked whether an association exists between disturbed platelet mitochondrial respiration and the plasma concentrations of Aβ40 and Aβ42 in patients with AD.Plasma Aβ40 and Aβ42 concentrations and mitochondrial respiration in intact and permeabilized platelets were measured in 50 patients with AD, 15 patients with vascular dementia and 25 control subjects. A pilot longitudinal study was performed to monitor the progression of AD in a subgroup 11 patients with AD.The mean Aβ40, Aβ42 and Aβ42/Aβ40 levels were not significantly altered in patients with AD compared with controls. The mitochondrial respiratory rate in intact platelets was significantly reduced in patients with AD compared to controls, particularly the basal respiratory rate, maximum respiratory capacity, and respiratory reserve; however, the flux control ratio for basal respiration was increased. A correlation between the plasma Aβ42 concentration and mitochondrial respiration in both intact and permeabilized platelets differs in controls and patients with AD.Based on our data, (1) mitochondrial respiration in intact platelets, but not the Aβ level itself, may be included in a panel of biomarkers for AD; (2) dysfunctional mitochondrial respiration in platelets is not explained by changes in plasma Aβ concentrations; and (3) the association between mitochondrial respiration in platelets and plasma Aβ levels differs in patients with AD and controls. The results supported the hypothesis that mitochondrial dysfunction is the primary factor contributing to the development of AD.Copyright © 2019. Published by Elsevier Inc.at mitochondrial dysfunction is the primary factor contributing to the development of AD. Copyright © 2019. Published by Elsevier Inc.)
Chowdhury 2018 Oxid Med Cell Longev + (Altered cellular metabolism is considered … Altered cellular metabolism is considered a hallmark of cancer and is fast becoming an avenue for therapeutic intervention. Mitochondria have recently been viewed as an important cellular compartment that fuels the metabolic demands of cancer cells. Mitochondria are the major source of ATP and metabolites necessary to fulfill the bioenergetics and biosynthetic demands of cancer cells. Furthermore, mitochondria are central to cell death and the main source for generation of reactive oxygen species (ROS). Overall, the growing evidence now suggests that mitochondrial bioenergetics, biogenesis, ROS production, and adaptation to intrinsic oxidative stress are elevated in chronic lymphocytic leukemia (CLL). Hence, recent studies have shown that mitochondrial metabolism could be targeted for cancer therapy. This review focuses the recent advancements in targeting mitochondrial metabolism for the treatment of CLL.drial metabolism for the treatment of CLL.)
Schoepf 2016 FEBS J + (Altered mitochondrial metabolism plays a p … Altered mitochondrial metabolism plays a pivotal role in the development and progression of various diseases, including cancer. Cell lines are frequently used as models to study mitochondrial (dys)function but little is known about their mitochondrial respiration and metabolic properties in comparison to the primary tissue of origin. We have developed a method for assessment of oxidative phosphorylation in prostate tissue samples of only 2 mg wet weight using high-resolution respirometry. Reliable protocols were established to investigate the respiratory activity of different segments of the mitochondrial electron transfer-pathway in mechanically permeabilized tissue biopsies. Additionally, the widely used immortalized prostate epithelial and fibroblast cell lines RWPE1 and NAF, representing the major cell types in prostate tissue, were analyzed and compared to the tissue of origin. Our results show that mechanical treatment without chemical permeabilization agents or sample processing constitutes a reliable preparation method for OXPHOS analysis in small amounts of prostatic tissue typically obtained by prostate biopsy. The cell lines represented the bioenergetic properties of fresh tissue to a limited extent only. Particularly, tissue showed a higher oxidative capacity with succinate and glutamate, whereas pyruvate was a substrate supporting significantly higher respiratory activities in cell lines. Several fold higher zinc levels measured in tissue compared to cells confirmed the role of aconitase for prostate specific metabolism in agreement with observed respiratory properties. In conclusion, combining the flexibility of cell culture models and tissue samples for respirometric analysis are powerful tools for investigation of mitochondrial function and tissue specific metabolism. n and tissue specific metabolism. )
Kupats 2020 Oxid Med Cell Longev + (Altered neuronal Ca2+</sup&g … Altered neuronal Ca2+ homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α2δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobutyric acid B (GABA-B) receptors. The aim of this study was to evaluate the potential therapeutic effects of R-phenibut following the lateral fluid percussion injury (latFPI) model of TBI in mice and the impact of R- and S-phenibut on mitochondrial functionality ''in vitro''. By determining the bioavailability of R-phenibut in the mouse brain tissue and plasma, we found that R-phenibut (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (i.p.) and peroral (p.o.) injections. The maximal concentration of R-phenibut in the brain tissues was 0.6 μg/g and 0.2 μg/g tissue after i.p. and p.o. administration, respectively. Male Swiss-Webster mice received i.p. injections of R-phenibut at doses of 10 or 50 mg/kg 2 h after TBI and then once daily for 7 days. R-Phenibut treatment at the dose of 50 mg/kg significantly ameliorated functional deficits after TBI on postinjury days 1, 4, and 7. Seven days after TBI, the number of Nissl-stained dark neurons (N-DNs) and interleukin-1beta (IL-1β) expression in the cerebral neocortex in the area of cortical impact were reduced. Moreover, the addition of R- and S-phenibut at a concentration of 0.5 μg/ml inhibited calcium-induced mitochondrial swelling in the brain homogenate and prevented anoxia-reoxygenation-induced increases in mitochondrial H2O2 production and the H2O2/O ratio. Taken together, these results suggest that R-phenibut could serve as a neuroprotective agent and promising drug candidate for treating TBI.erve as a neuroprotective agent and promising drug candidate for treating TBI.)
Porter 2015 Burns + (Altered skeletal muscle mitochondrial func … Altered skeletal muscle mitochondrial function contributes to the pathophysiological stress response to burns. However, the acute and chronic impact of burn trauma on skeletal muscle bioenergetics remains poorly understood. Here, we determined the temporal relationship between burn trauma and mitochondrial function in murine skeletal muscle local to and distal from burn wounds. Male BALB/c mice (8-10 weeks old) were burned by submersion of the dorsum in water (∼95°C) to create a full thickness burn on ∼30% of the body. Skeletal muscle was harvested spinotrapezius underneath burn wounds (local) and the quadriceps (distal) of sham and burn treated mice at 3h, 24h, 4d and 10d post-injury. Mitochondrial respiration was determined in permeabilized myofiber bundles by high-resolution respirometry. Caspase 9 and caspase 3 protein concentration were determined by western blot. In muscle local to burn wounds, respiration coupled to ATP production was significantly diminished at 3h and 24h post-injury (''P''<0.001), as was mitochondrial coupling control (''P''<0.001). There was a 5- (''P''<0.05) and 8-fold (''P''<0.001) increase in respiration in response to cytochrome at 3h and 24h post burn, respectively, indicating damage to the outer mitochondrial membranes. Moreover, we also observed greater active caspase 9 and caspase 3 in muscle local to burn wounds, indicating the induction of apoptosis. Distal muscle mitochondrial function was unaltered by burn trauma until 10d post burn, where both respiratory capacity (''P''<0.05) and coupling control (''P''<0.05) were significantly lower than sham. These data highlight a differential response in muscle mitochondrial function to burn trauma, where the timing, degree and mode of dysfunction are dependent on whether the muscle is local or distal to the burn wound. on whether the muscle is local or distal to the burn wound.)
Krischek 2016 Mol Reprod Dev + (Altering incubation temperature during emb … Altering incubation temperature during embryogenesis has an impact on chicken embryo growth, but the underlying molecular mechanisms are not understood; the present study was performed to address these changes. Broiler eggs were incubated at low (36.8°C), control (37.8°C), and high (38.8°C) temperatures between Embryonic Day (ED) 7 and 10 or ED 10 and 13, which cover critical periods of embryonic myogenesis. The embryos were then dissected immediately after treatment on ED 10 or 13 to assess body, liver, and heart weights as well as to analyze breast and leg muscle fibers for their mitochondrial respiratory activity (MRA). Breast muscle samples were additionally used to evaluate the activity of enzymes involved in energy metabolism and cell-cycle progression. ED-10 embryos incubated at 38.8°C showed elevated weights (body, liver, and heart), MRA, and activities of lactate dehydrogenase and cytochrome oxidase compared to the ED-10 embryos incubated at 36.8°C. Similarly, the ED-13 embryos incubated at 38.8°C showed elevated body weight, MRA, and activities of glycogen phosphorylase, phosphofructokinase, and cytochrome oxidase compared to their 36.8°C counterparts. Embryos incubated at the normal temperature (37.8°C), however, showed variable differences from those incubated at 38.8°C versus 36.8°C. Cell-cycle enzyme activities were not impacted by the different temperature treatments. Thus, an increase or decrease in the incubation temperature during embryonic broiler myogenesis results in altered embryo activity, muscle energy metabolism, and activity-dependent muscle growth.ism, and activity-dependent muscle growth.)
Oparka 2014 Abstract MiP2014 + (Alternations of pivotal mitochondrial func … Alternations of pivotal mitochondrial function – oxidative phosphorylation as well as abnormal cellular ROS production - can potentially be responsible for pathogenesis of cancer. In the last years, implications of p66Shc adaptor protein in the cellular response to oxidative stress have been discovered. Involvement of this protein in cell death is related to oxidative stress. Phosphorylation of p66Shc at Ser36 can be activated by extracellular or intracellular reactive oxygen species (ROS), and an initiated cascade of events is finally involved in the amplification of mitochondrial ROS production. The available literature does not contain a lot of data concerning the role of p66shc and its Ser36 phosphorylation in tumorigenesis and cancer growth. Therefore, we studied the relationship between ROS production, antioxidant defense systems and the level of p66Shc as well as p66Shc phosphorylation in murine cancer cell lines, derived from ectoderm (B16-F10, B78, MmB16, EMT6, 4T1), mesoderm (Renca) and endoderm (CT26.WT, Hepa1-6, LLC, Panc02).The cancer cells exhibited various levels of p66Shc and its Ser36 phosphorylation, which simultaneously is negatively correlated with the level of superoxide dismutase 2 in some of the investigated cancer cell lines. ROS can mediate opposing cellular functions like cell proliferation and apoptosis. In turn, p66Shc Ser36 phosphorylation pathway is involved in regulation of mitochondrial metabolism and is responsible for elevated intracellular ROS levels. Moreover, p66Shc seems to play an important role in cancer metastasis and cancer cell adhesion. This emphasizes the importance of understanding the mechanisms and sites of ROS formation in cancer cells, the role of p66Shc in this process and the effect on tumor physiology.Supported by Statutory Founding from Nencki Institute of Experimental Biology and Polish Ministry of Science and Higher Education grant W100/HFSC/2011.and Higher Education grant W100/HFSC/2011.)
Polajnar 2014 PLOS ONE + (Alternative functions, apart from cathepsi … Alternative functions, apart from cathepsins inhibition, are being discovered for stefin B. Here, we investigate its role in vesicular trafficking and autophagy. Astrocytes isolated from stefin B knock-out (KO) mice exhibited an increased level of protein aggregates scattered throughout the cytoplasm. Addition of stefin B monomers or small oligomers to the cell medium reverted this phenotype, as imaged by confocal microscopy. To monitor the identity of proteins embedded within aggregates in wild type (wt) and KO cells, the insoluble cell lysate fractions were isolated and analyzed by mass spectrometry. Chaperones, tubulins, dyneins, and proteosomal components were detected in the insoluble fraction of wt cells but not in KO aggregates. In contrast, the insoluble fraction of KO cells exhibited increased levels of apolipoprotein E, fibronectin, clusterin, major prion protein, and serpins H1 and I2 and some proteins of lysosomal origin, such as cathepsin D and CD63, relative to wt astrocytes. Analysis of autophagy activity demonstrated that this pathway was less functional in KO astrocytes. In addition, synthetic dosage lethality (SDL) gene interactions analysis in ''Saccharomyces cerevisiae'' expressing human stefin B suggests a role in transport of vesicles and vacuoles These activities would contribute, directly or indirectly to completion of autophagy in wt astrocytes and would account for the accumulation of protein aggregates in KO cells, since autophagy is a key pathway for the clearance of intracellular protein aggregates.rance of intracellular protein aggregates.)
Rajendran 2019 EMBO Mol Med + (Alternative oxidase (AOX) is a non-mammali … Alternative oxidase (AOX) is a non-mammalian enzyme that can bypass blockade of the complex III-IV segment of the respiratory chain (RC). We crossed a Ciona intestinalis AOX transgene into RC complex III (cIII)-deficient Bcs1lp.S78G knock-in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable, and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific pathogenetic mechanisms. Assessment of reactive oxygen species (ROS) production and damage suggested that ROS were not instrumental in the rescue. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis and detrimental decompensation. These findings demonstrate the value of AOX, both as a mechanistic tool and a potential therapeutic strategy, for cIII deficiencies.© 2018 The Authors. Published under the terms of the CC BY 4.0 license. Published under the terms of the CC BY 4.0 license.)
Robertson 2016 J Bioenerg Biomembr + (Alternative oxidase (AOX) is a terminal ox … Alternative oxidase (AOX) is a terminal oxidase within the inner mitochondrial membrane (IMM) present in many organisms where it functions in the electron transport system (ET-pathway). AOX directly accepts electrons from ubiquinol and is therefore capable of bypassing ET-pathway Complexes III and IV. The human genome does not contain a gene coding for AOX, so AOX expression has been suggested as a gene therapy for a range of human mitochondrial diseases caused by genetic mutations that render Complex III and/or IV dysfunctional. An effective means of screening mutations amenable to AOX treatment remains to be devised. We have generated such a tool by heterologously expressing AOX from the Pacific oyster (''Crassostrea gigas'') in the yeast ''Saccharomyces cerevisiae'' under the control of a galactose promoter. Our results show that this animal AOX is monomeric and is correctly targeted to yeast mitochondria. Moreover, when expressed in yeast, Pacific oyster AOX is a functional quinol oxidase, conferring cyanide-resistant growth and myxothiazol-resistant oxygen consumption to yeast cells and isolated mitochondria. This system represents a high-throughput screening tool for determining which Complex III and IV genetic mutations in yeast will be amenable to AOX gene therapy. As many human genes are orthologous to those found in yeast, our invention represents an efficient and cost-effective way to evaluate viable research avenues. In addition, this system provides the opportunity to learn more about the localization, structure, and regulation of AOXs from animals that are not easily reared or manipulated in the lab.t easily reared or manipulated in the lab.)
McDonald 2011 Abstract IOC65 + (Alternative oxidase (AOX) is a ubiquinol t … Alternative oxidase (AOX) is a ubiquinol terminal oxidase present in the respiratory electron transport chains of a wide variety of organisms [1]. AOX by-passes 2 of the 3 proton pumping complexes in the respiratory chain and therefore makes respiration less efficient in terms of the amount of ATP generated per oxygen consumed. Our previous work using bioinformatics has revealed the presence of AOX genes in eukaryotic organisms such as plants, animals, fungi, algae, and protists, as well as in prokaryotes in several species of eubacteria [2]. Recent work using reverse transcriptase polymerase chain reaction (RT-PCR) experiments has demonstrated that these genes are transcribed in many organisms [3]. Our focus is now shifting to exploring the respiratory capacity of AOX proteins in these different systems and in identifying how the activity of AOX proteins is regulated at the post-translational level.regulated at the post-translational level.)
Dogan 2018 Cell Metab + (Alternative oxidases (AOXs) bypass respira … Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O2. They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout (KO) mouse with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared with KO alone. Decreased ROS production in KO-AOX versus KO mice led to impaired AMPK/PGC-1α signaling and PAX7/MYOD-dependent muscle regeneration, blunting compensatory responses. Importantly, the antioxidant N-acetylcysteine had a similar effect, decreasing the lifespan of KO mice. Our findings have major implications for understanding pathogenic mechanisms in mitochondrial diseases and for the design of therapies, highlighting the benefits of ROS signaling and the potential hazards of antioxidant treatment.ng and the potential hazards of antioxidant treatment.)
Moreno-Ortega 2016 Neurotox Res + (Alternatives for the treatment of amyotrop … Alternatives for the treatment of amyotrophic lateral sclerosis (ALS) are scarce and controversial. The etiology of neuronal vulnerability in ALS is being studied in motor neuron-like NSC-34 cells to determine the underlying mechanisms leading to selective loss of motor neurons. One such mechanism is associated with mitochondrial oxidative stress, Ca2+ overload, and low expression of Ca2+-buffering proteins. Therefore, in order to elicit neuronal death in ALS, NSC-34 cells were exposed to the following cytotoxic agents: (1) a mixture of oligomycin 10 µM and rotenone 30 µM (O/R), or (2) phenylarsine oxide 1 µM (PAO) (to mimic excess free radical production during mitochondrial dysfunction), and (3) veratridine 100 µM (VTD) (to induce overload of Na(+) and Ca2+ and to alter distribution of Ca2+-buffering proteins [parvalbumin and calbindin-D28k]). Thus, the aim of the study was to test the novel neuroprotective compound ITH33/IQM9.21 (ITH33) and to compare it with riluzole on ''in vitro'' models of neurotoxicity. Cell viability measured with MTT showed that only ITH33 protected against O/R at 3 μM and PAO at 10 μM, but not riluzole. ITH33 and riluzole were neuroprotective against VTD, blocked the maximum peak and the number of [Ca2+]c oscillations per cell, and restored the effect on parvalbumin. However, only riluzole reversed the effect on calbindin-D28k levels. Therefore, ITH33 was neuroprotective against oxidative stress and Na+/Ca2+ overload, both of which are involved in ALS.ainst oxidative stress and Na+/Ca2+ overload, both of which are involved in ALS.)
Irving 2022 Abstract Bioblast + (Although Alzheimer's disease (AD)'s underl … Although Alzheimer's disease (AD)'s underlying pathophysiology is incompletely understood, reductions in mitochondrial bioenergetics are observed during AD development. Reductions in nitric oxide (NO) bioavailability can reduce cerebral blood flow, promote the deposition of β-amyloid (Aβ), and contribute to mitochondrial dysfunction. However, pathological elevations in NO can also inhibit mitochondrial respiration and mitochondrial quality control. High-Fat Diets (HFD) are associated with reductions in NO bioavailability and AD development. Therefore, we sought to investigate the effects of dietary NO donors (Na+-nitrite and citrulline) on mitochondrial bioenergetics in female APPswe/PS1dE9 (APP/PS1) fed a HFD.We fed 10-week-old APP/PS1 transgenic mice, and their littermate controls (wild-type, WT) either a normal chow diet, HFD, or HFD supplemented with a NO promoter (Na+-nitrite or L-citrulline) for six months. Specifically, 100 mg/L Na+-nitrite or 2.5 mM L-citrulline was provided in their drinking water. The mice were euthanized, and the hypothalami were carefully dissected out and placed in ice-cold BIOPS. The hypothalami were homogenized in a mitochondrial respiration media (MiR05-Kit, pH 7.1).We used high-resolution respirometry (HRR, Oroboros O2k) coupled with a standardized substrate-uncoupler-inhibitor-titration (SUIT) protocol to measure respiration rates in duplicate during LEAK (State 4), OXPHOS capacity (State 3), and electron transfer capacity (ET) states in permeabilized hypothalami homogenates at 37 °C and O2 concentrations between ~450 µM and ~150 µM. We supplement the MiR05 with α-chaconine (40 µM) to chemically permeabilize the plasma membranes and synaptosomes. First, we measured NADH-linked LEAK respiration (N''L'') in the presence of pyruvate (5 mM), malate (2 mM), and glutamate (10 mM) in the absence of ADP. We measured NADH-Linked OXPHOS (N''P'') following the addition of a saturating concentration of ADP-Mg++ (5 mM). Next, we assessed the mitochondrial membrane integrity using cytochrome ''c'' (10 µM). We measured NS-linked OXPHOS (NS''P'') after the addition of succinate (10 mM). Next, we titrated in carbonyl cyanide m-chlorophenyl hydrazine (CCCP) (0.5 µM/step) to achieve NS-linked ET capacity (NS''E''). Next, we titrated rotenone (0.5 µM) to measure succinate-linked ET capacity (S''E''), followed by the titration of glycerol-3-phosphate (15 mM) to measure SGp-linked ET capacity (SGp''E''). Finally, we added antimycin A (2.5 µM) to measure residual oxygen consumption (''Rox''). The respiration rates were normalized per mg mass [pmol·s-1·mg-1], referred to as oxygen flux (''J''O2).The final body and fat masses of HFD-fed APP/PS1 mice (48.2 g & 17.7 g) were significantly higher than those of HFD-fed WT mice (42.4 g & 14.3 g). NO donors (Na+-nitrite or citrulline) had no effect on body mass or fat mass. There was a significant group effect (''p''<0.05) effect on OXPHOS and ET capacity. Specifically, the APS/PS1 mice had significantly lower OXPHOS and ET capacity while on the HFD compared to WT. The NO donors (Na+-nitrite or citrulline) could rescue the OXPHOS and ET capacity in the APS/PS1 mice fed a HFD.In summary, the APS/PS1 mice had lower OXPHOS and ET capacity than their WT controls while on an HFD. Physiologically relevant NO donors may provide an opportunity to mitigate some of the negative consequences of AD pathology.n the APS/PS1 mice fed a HFD. In summary, the APS/PS1 mice had lower OXPHOS and ET capacity than their WT controls while on an HFD. Physiologically relevant NO donors may provide an opportunity to mitigate some of the negative consequences of AD pathology.)
Khrameeva 2014 Nat Commun + (Although Neanderthals are extinct, fragmen … Although Neanderthals are extinct, fragments of their genomes persist in contemporary humans. Here we show that while the genome-wide frequency of Neanderthal-like sites is approximately constant across all contemporary out-of-Africa populations, genes involved in lipid catabolism contain more than threefold excess of such sites in contemporary humans of European descent. Evolutionally, these genes show significant association with signatures of recent positive selection in the contemporary European, but not Asian or African populations. Functionally, the excess of Neanderthal-like sites in lipid catabolism genes can be linked with a greater divergence of lipid concentrations and enzyme expression levels within this pathway, seen in contemporary Europeans, but not in the other populations. We conclude that sequence variants that evolved in Neanderthals may have given a selective advantage to anatomically modern humans that settled in the same geographical areas.at settled in the same geographical areas.)
Gnecchi-Ruscone 2018 Genome Biol Evol + (Although Tibetans and Sherpa present sever … Although Tibetans and Sherpa present several physiological adjustments evolved to cope with selective pressures imposed by the high altitude environment, especially hypobaric hypoxia, few selective sweeps at a limited number of hypoxia related genes were confirmed by multiple genomic studies. Nevertheless, variants at these loci were found to be associated only with downregulation of the erythropoietic cascade, which represents an indirect aspect of the considered adaptive phenotype. Accordingly, the genetic basis of Tibetan/Sherpa adaptive traits remains to be fully elucidated, in part due to limitations of selection scans implemented so far and mostly relying on the hard sweep model.In order to overcome this issue, we used whole genome sequence data and several selection statistics as input for gene network analyses aimed at testing for the occurrence of polygenic adaptation in these high-altitude Himalayan populations. Being able to detect also subtle genomic signatures ascribable to weak positive selection at multiple genes of the same functional subnetwork, this approach allowed us to infer adaptive evolution at loci individually showing small effect sizes, but belonging to highly interconnected biological pathways overall involved in angiogenetic processes.Therefore, these findings pinpointed a series of selective events neglected so far, which likely contributed to the augmented tissue blood perfusion observed in Tibetans and Sherpa, thus uncovering the genetic determinants of a key biological mechanism that underlies their adaptation to high altitude.derlies their adaptation to high altitude.)
Becker 1999 Am J Physiol + (Although a burst of oxidants has been well … Although a burst of oxidants has been well described with reperfusion, less is known about the oxidants generated by the highly reduced redox state and low O(2) of ischemia. This study aimed to further identify the species and source of these oxidants. Cardiomyocytes were exposed to 1 h of simulated ischemia while oxidant generation was assessed by intracellular dihydroethidine (DHE) oxidation. Ischemia increased DHE oxidation significantly (0.7 +/- 0.1 to 2.3 +/- 0.3) after 1 h. Myxothiazol (mitochondrial site III inhibitor) attenuated oxidation to 1.3 +/- 0.1, as did the site I inhibitors rotenone (1.0 +/- 0.1), amytal (1.1 +/- 0.1), and the flavoprotein oxidase inhibitor diphenyleneiodonium (0.9 +/- 0.1). By contrast, the site IV inhibitor cyanide, as well as inhibitors of xanthine oxidase (allopurinol), nitric oxide synthase (nitro-L-arginine methyl ester), and NADPH oxidase (apocynin), had no effect. Finally, DHE oxidation increased with Cu- and Zn-containing superoxide dismutase (SOD) inhibition using diethyldithiocarbamate (2.7 +/- 0.1) and decreased with exogenous SOD (1.1 +/- 0.1). We conclude that significant superoxide generation occurs during ischemia before reperfusion from the ubisemiquinone site of the mitochondrial electron transport chain.he mitochondrial electron transport chain.)

(Although a burst of oxidants has been well described with reperfusion, l)

Kilbaugh 2015 J Am Heart Assoc + (Although advances in cardiopulmonary resus … Although advances in cardiopulmonary resuscitation have improved survival from cardiac arrest (CA), neurologic injury persists and impaired mitochondrial bioenergetics may be critical for targeted neuroresuscitation. The authors sought to determine if excellent cardiopulmonary resuscitation and postresuscitation care and good traditional survival rates result in persistently disordered cerebral mitochondrial bioenergetics in a porcine pediatric model of asphyxia-associated ventricular fibrillation CA.After 7 minutes of asphyxia, followed by ventricular fibrillation, 5 female 1-month-old swine (4 sham) received blood pressure-targeted care: titration of compression depth to systolic blood pressure of 90 mm Hg and vasopressor administration to a coronary perfusion pressure >20 mm Hg. All animals received protocol-based vasopressor support after return of spontaneous circulation for 4 hours before they were killed. The primary outcome was integrated mitochondrial electron transport system (ET-pathway) function. CA animals displayed significantly decreased maximal, coupled oxidative phosphorylating respiration (OXPHOSCI + CII) in cortex (P<0.02) and hippocampus (P<0.02), as well as decreased phosphorylation and coupling efficiency (cortex, P<0.05; hippocampus, P<0.05). Complex I- and complex II-driven respiration were both significantly decreased after CA (cortex: OXPHOSCI P<0.01, ETSCII P<0.05; hippocampus: OXPHOSCI P<0.03, ETSCII P<0.01). In the hippocampus, there was a significant decrease in maximal uncoupled, nonphosphorylating respiration (ETSCI + CII), as well as a 30% reduction in citrate synthase activity (P<0.04).Mitochondria in both the cortex and hippocampus displayed significant alterations in respiratory function after CA despite excellent cardiopulmonary resuscitation and postresuscitation care in asphyxia-associated ventricular fibrillation CA. Analysis of integrated ET-pathway function identifies mitochondrial bioenergetic failure as a target for goal-directed neuroresuscitation after CA. IACUC Protocol: IAC 13-001023.oal-directed neuroresuscitation after CA. IACUC Protocol: IAC 13-001023.)
Spinelli 2018 Nat Cell Biol + (Although classically appreciated for their … Although classically appreciated for their role as the powerhouse of the cell, the metabolic functions of mitochondria reach far beyond bioenergetics. In this Review, we discuss how mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis and function as hubs for metabolic waste management. We address the importance of these roles in both normal physiology and in disease. in both normal physiology and in disease.)
Sanchez 2001 Br J Pharmacol + (Although cyclosporin (CsA) is considered t … Although cyclosporin (CsA) is considered to be the best immunosuppressive molecule in transplantation, it has been suspected to alter mitochondrial respiration of various tissues.We evaluated the acute effect of CsA and its vehicle on maximal oxidative capacity (Vmax) of cardiac, soleus and gastrocnemius muscles of rats by an oxygraphic method in saponin skinned muscle fibres. The effects of Sandimmun (a formulation of CsA), vehicle of Sandimmun (cremophor and ethanol (EtOH)), CsA in EtOH and EtOH alone were tested. Increasing concentrations (5 – 20 – 50 – 100 μM) of CsA (or vehicles) were used.Sandimmun profoundly altered the Vmax of all muscles. For example, at 20 μM, inhibition reached 18±3, 23±5, 45±5%, for heart, soleus and gastrocnemius respectively. There were only minor effects of CsA diluted in EtOH and EtOH alone on Vmax of cardiac muscle. Because the effects of vehicle on Vmax were similar or higher than those of Sandimmun, the inhibition of oxidative capacity could be entirely attributed to the vehicle for all muscles.Next, we investigated the potential sites of action of the vehicle on the different complexes of the mitochondrial respiratory chain by using specific substrates and inhibitors. The vehicle affected mitochondrial respiration mainly at the level of complex I (≈−85 % in skeletal muscles, and −32 % in heart), but also at complex IV (≈−26 % for all muscles).The mechanism of action of the vehicle on the mitochondrial membrane and the implications for the clinical use of immunosuppressive drugs are discussed. of immunosuppressive drugs are discussed.)
Belosludtsev 2019 Cells + (Although diabetes mellitus is known to be … Although diabetes mellitus is known to be a disease associated with mitochondrial dysfunction, not everything is clear about mitochondrial Ca2+ transport and Ca2+-induced permeability transition in diabetic cells. The objective of this work was to study the operation of MCU and Ca2+-dependent mitochondrial permeabilization in the liver cells of Sprague-Dawley rats under the streptozotocin-induced type I diabetes. It was shown that two weeks after the induction of diabetes, the rate of Ca2+ uptake by the mitochondria of diabetic animals increased ~1.4-fold. The expression of MCU and MICU1 subunits did not change, yet the quantity of dominant-negative MCUb channel subunits was almost twice as lower. The organelles also became more resistant to the induction of CsA-sensitive MPT pore and less resistant to the induction of CsA-insensitive palmitate/Ca2+-induced pore. The mitochondria of diabetic liver cells also showed changes in the lipid matrix of their membranes. The content of fatty acids in the membranes grew, and microviscosity of the lipid bilayer (assessed with laurdan) increased. At the same time, lipid peroxidation (assessed by the production of malonic dialdehyde) was stimulated. The paper discusses the consequences of the diabetes-related changes in mitochondria in the context of cell physiology.es the consequences of the diabetes-related changes in mitochondria in the context of cell physiology.)
Lee 2023 Antioxidants (Basel) + (Although elevated cholesterol and other re … Although elevated cholesterol and other recognised cardiovascular risk factors are important in the development of coronary artery disease (CAD) and heart attack, the susceptibility of humans to this fatal process is distinct from other animals. Mitochondrial dysfunction of cells in the arterial wall, particularly the endothelium, has been strongly implicated in the pathogenesis of CAD. In this manuscript, we review the established evidence and mechanisms in detail and explore the potential opportunities arising from analysing mitochondrial function in patient-derived cells such as endothelial colony-forming cells easily cultured from venous blood. We discuss how emerging technology and knowledge may allow us to measure mitochondrial dysfunction as a potential biomarker for diagnosis and risk management. We also discuss the "pros and cons" of animal models of atherosclerosis, and how patient-derived cell models may provide opportunities to develop novel therapies relevant for humans. Finally, we review several targets that potentially alleviate mitochondrial dysfunction working both via direct and indirect mechanisms and evaluate the effect of several classes of compounds in the cardiovascular context.f compounds in the cardiovascular context.)
Koncsos 2016 Am J Physiol Heart Circ Physiol + (Although incidence and prevalence of predi … Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria.tress originates from the subsarcolemmal mitochondria.)
Wang 2019 Free Radic Biol Med + (Although insulin-like growth factor-1 rece … Although insulin-like growth factor-1 receptor (IGF-1R) has been accepted as a major determinant of cancers, its biological roles and corresponding mechanisms in tumorigenesis have remained elusive. Herein, we demonstrate that IGF-1R plays pivotal roles in the regulation of mitochondrial respiratory chain and functions during colitis and tumorigenesis. Heterozygous knockout IGF-1R attenuated azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and colitis associated cancer (CAC) in Igf1r+/- mice. Heterozygous knockout IGF-1R confers resistance to oxidative stress-induced damage on colorectal epithelial cells by protecting mitochondrial dynamics and structures. IGF-1R low expression improves the biological function of mitochondrial fusion under oxidative stress. Mechanically, an increase in respiratory coupling index (RCI) and oxidative phosphorylation index (ADP/O) was seen in colorectal epithelial cells of Igf1r+/- mice. Seahorse XFe-24 analyzer analysis of mitochondrial bioenergetics demonstrated an increase in oxygen consumption rate (OCR) and a decrease of extracellular acidification rate (ECAR) in Igf1r+/- cells. Further analysis suggests the protection mechanisms of Igf1r+/- cells from oxidative stress through the activation of the mitochondrial respiratory chain and LKB1/AMPK pathways. These results highlight the biological roles of IGF-1R at the nexus between oxidative damage and mitochondrial function and a connection between colitis and colorectal cancer.Copyright © 2019 Elsevier Inc. All rights reserved.een colitis and colorectal cancer. Copyright © 2019 Elsevier Inc. All rights reserved.)
Marchi 2014 J Physiol + (Although it has long been known that mitoc … Although it has long been known that mitochondria take up Ca2+, the molecular identities of the channels and transporters involved in this process were revealed only recently. Here, we discuss the recent work that has led to the characterization of the mitochondrial calcium uniporter complex, which includes the channel-forming subunit MCU (mitochondrial calcium uniporter) and its regulators MICU1, MICU2, MCUb, EMRE, MCUR1 and miR-25. We review not only the biochemical identities and structures of the proteins required for mitochondrial Ca2+ uptake but also their implications in different physiopathological contexts. in different physiopathological contexts.)
Cai 2021 Free Radic Biol Med + (Although it is well known that selective i … Although it is well known that selective intra-arterial cooling (SI-AC) elicits cerebral protection against ischemia/reperfusion (I/R) injury, the underlying mechanism remains unclear. This study aimed to determine whether SI-AC can protect against cerebral I/R injury by inhibiting oxidative stress and mitochondrial dysfunction through regulation of Sirt3 deSUMOylation via SENP1.All mice were subjected to 2 h of cerebral ischemia followed by 24 h of reperfusion. SI-AC treatment was performed by infusion with cold saline (10 °C, 20 mL/kg) for 15 min through a microcatheter placed in the internal carotid artery immediately before reperfusion. The infarct volume, survival rate, neurological deficit scores, behavioral parameters, histopathology findings, and apoptosis were assessed. HT22 cells were subjected to 2 h of oxygen and sugar deprivation (OGD) and 22 h of reoxygenation. HA-SUMO1, Flag-Sirt3, a Sirt3 mutation plasmid (Flag-Sirt3 K288R), His-SENP1, and SENP1 small interfering RNA were transfected into HT22 cells 48 h before OGD. Apoptosis-related proteins were analyzed by western blotting. SUMOylation of Sirt3, acetylation of cyclooxygenase 1 (COX1), superoxide dismutase 2 (SOD2), and isocitrate dehydrogenase 2 (IDH2), the activities of COX1, SOD2, and IDH2, oxidative stress, and mitochondrial dysfunction were evaluated.Compared with the I/R group, SI-AC decreased cerebral infarct volume and neurological deficit scores and increased motor coordination, exploratory behavior, and memory. Hematoxylin and eosin and Nissl staining showed that SI-CA decreased karyopyknosis, nuclear fragmentation, and nucleolysis, increased neuron density, and decreased the cell apoptosis rate. In addition, Sirt3 was revealed as a target protein of SUMO1. SI-AC attenuated cerebral I/R injury through Sirt3 deSUMOylation via SENP1.SENP1-mediated deSUMOylation of Sirt3 plays an essential role in SI-AC-induced cerebral protection against I/R injury. Our findings provide a promising therapeutic approach for treatment of acute cerebral I/R injury.or treatment of acute cerebral I/R injury.)
Xiao 2019 Int J Hypertens + (Although many researches regarding risk fa … Although many researches regarding risk factors for hypertension have been reported, little information is known about the effect of BMI on the prevalence of hypertension considering sex differences. The aim of this study was to examine the sex difference in the prevalence of hypertension with the predicting indicator BMI. A total number of 6330 subjects in Shaanxi were examined using multivariable logistic regression to study the relationship between genders in different levels of BMI and prevalence of hypertension. Overall, females had a higher prevalence of hypertension than males, being 28.36 % and 21.55 %, respectively. The mean of blood pressure and the prevalence of hypertension increased as BMI getting larger. The result of multivariable logistic regression showed that obese and overweight males had higher risk of getting hypertension than their female counterparts. Further prevention of hypertension should be focused on obese and overweight males more than females and examining the mechanism of how sex differences influence the prevalence of hypertension. influence the prevalence of hypertension.)
Hom 2011 Dev Cell + (Although mature myocytes rely on mitochond … Although mature myocytes rely on mitochondria as the primary source of energy, the role of mitochondria in the developing heart is not well known. Here, we find that closure of the mitochondrial permeability transition pore (mPTP) drives maturation of mitochondrial structure and function and myocyte differentiation. Cardiomyocytes at embryonic day (E) 9.5, when compared to E13.5, displayed fragmented mitochondria with few cristae, a less-polarized mitochondrial membrane potential, higher reactive oxygen species (ROS) levels, and an open mPTP. Pharmacologic and genetic closing of the mPTP yielded maturation of mitochondrial structure and function, lowered ROS, and increased myocyte differentiation (measured by counting Z bands). Furthermore, myocyte differentiation was inhibited and enhanced with oxidant and antioxidant treatment, respectively, suggesting that redox-signaling pathways lie downstream of mitochondria to regulate cardiac myocyte differentiation. regulate cardiac myocyte differentiation.)
Gupta 2021 Sci Rep + (Although microRNA-7 (miRNA-7) is known to … Although microRNA-7 (miRNA-7) is known to regulate proliferation of cancer cells by targeting Epidermal growth factor receptor (EGFR/ERBB) family, less is known about its role in cardiac physiology. Transgenic (Tg) mouse with cardiomyocyte-specific overexpression of miRNA-7 was generated to determine its role in cardiac physiology and pathology. Echocardiography on the miRNA-7 Tg mice showed cardiac dilation instead of age-associated physiological cardiac hypertrophy observed in non-Tg control mice. Subjecting miRNA-7 Tg mice to transverse aortic constriction (TAC) resulted in cardiac dilation associated with increased fibrosis bypassing the adaptive cardiac hypertrophic response to TAC. miRNA-7 expression in cardiomyocytes resulted in significant loss of ERBB2 expression with no changes in ERBB1 (EGFR). Cardiac proteomics in the miRNA-7 Tg mice showed significant reduction in mitochondrial membrane structural proteins compared to NTg reflecting role of miRNA-7 beyond the regulation of EGFR/ERRB in mediating cardiac dilation. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized rounded mitochondria that was associated with mitochondrial dysfunction. These findings show that expression of miRNA-7 in the cardiomyocytes results in cardiac dilation instead of adaptive hypertrophic response during aging or to TAC providing insights on yet to be understood role of miRNA-7 in cardiac function.stood role of miRNA-7 in cardiac function.)
Kamunde 2018 Free Radic Biol Med + (Although mitochondria are presumed to emit … Although mitochondria are presumed to emit and consume reactive oxygen species (ROS), the quantitative interplay between the two processes in ROS regulation is not well understood. Here, we probed the role of mitochondrial bioenergetics in H2O2 metabolism using rainbow trout liver and heart mitochondria. Both liver and heart mitochondria emitted H2O2 at rates that depended on their metabolic state, with the emission rates (free radical leak) constituting 0.8-2.9% and 0.2-2.5% of the respiration rate in liver and heart mitochondria, respectively. When presented with exogenous H2O2, liver and heart mitochondria consumed it by first order reactions with half-lives (s) of 117 and 210, and rate constants of 5.96 and 3.37 (× 10-3 s-1), respectively. The mitochondrial bioenergetic status greatly affected the rate of H2O2 consumption in heart but not liver mitochondria. Moreover, the activities and contribution of H2O2 scavenging systems varied between liver and heart mitochondria. The significance of the scavenging systems ranked by the magnitude (%) of inhibition of H2O2 removal after correcting for emission were, liver (un-energized and energized): catalase > glutathione (GSH) ≥ thioredoxin reductase (TrxR); un-energized heart mitochondria: catalase > TrxR > GSH and energized heart mitochondria: GSH > TrxR > catalase. Notably, depletion of GSH evoked a massive surge in H2O2 emission that grossly masked the contribution of this pathway to H2O2 scavenging in heart mitochondria. Irrespective of the organ of their origin, mitochondria behaved as H2O2 regulators that emitted or consumed it depending on the ambient H2O2 concentration, mitochondrial bioenergetic state and activity of the scavenging enzyme systems. Indeed, manipulation of mitochondrial bioenergetics and H2O2 scavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.cavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.)
MacDonald 2018 IOC130 + (Although mitochondria are presumed to emit … Although mitochondria are presumed to emit and consume reactive oxygen species (ROS), the quantitative interplay between the two processes in ROS regulation is not well understood. Here, we probed the role of mitochondrial bioenergetics in H2O2 metabolism using rainbow trout liver and heart mitochondria. Both liver and heart mitochondria emitted H2O2 at rates that depended on their metabolic state, with the emission rates (free radical leak) constituting 0.8 to 2.9% and 0.2 to 2.5% of the respiration rate in liver and heart mitochondria, respectively. When presented with exogenous H2O2, liver and heart mitochondria consumed it by first order reactions with half-lives (s) of 117 and 210, and rate constants of 5.96 and 3.37 (× 10-3 s-1), respectively. The mitochondrial bioenergetic status greatly affected the rate of H2O2 consumption in heart but not liver mitochondria. Moreover, the activities and contribution of H2O2 scavenging systems varied between liver and heart mitochondria. The significance of the scavenging systems ranked by the magnitude (%) of inhibition of H2O2 removal after correcting for emission were, liver (un-energized and energized): catalase > glutathione (GSH) ≥ thioredoxin reductase (TrxR); un-energized heart mitochondria: catalase > TrxR > GSH and energized heart mitochondria: GSH > TrxR > catalase. Notably, depletion of GSH evoked a massive surge in H2O2 emission that grossly masked the contribution of this pathway to H2O2 scavenging in heart mitochondria. Irrespective of the organ of their origin, mitochondria behaved as H2O2 regulators that emitted or consumed it depending on the ambient H2O2 concentration, mitochondrial bioenergetic state and activity of the scavenging enzyme systems. Indeed, manipulation of mitochondrial bioenergetics and H2O2 scavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.cavenging systems caused mitochondria to switch from being net consumers to net emitters of H2O2. Overall, our data suggest that the low levels of H2O2 typically present in cells would favor emission of this metabolite but the scavenging systems would prevent its accumulation.)
Jardim-Messeder 2022 Biochim Biophys Acta Bioenerg + (Although mitochondria have a central role … Although mitochondria have a central role in energy transduction and reactive oxygen species (ROS) production, the regulatory mechanisms and their involvement in plant stress signaling are not fully established. The phytohormone salicylic acid (SA) is an important regulator of mitochondria-mediated ROS production and defense signaling. The role of SA and adenine nucleotides in the regulation of the mitochondrial succinate dehydrogenase (SDH) complex activity and ROS production was analyzed using WT, RNAi SDH1-1 and disrupted stress response 1 (dsr1) mutants, which show a point mutation in SDH1 subunit and are defective in SA signaling. Our results showed that SA and adenine nucleotides regulate SDH complex activity by distinct patterns, contributing to increased SDH-derived ROS production. As previously demonstrated, SA induces the succinate-quinone reductase activity of SDH complex, acting at or near the ubiquinone binding site. On the other hand, here we demonstrated that adenine nucleotides, such as AMP, ADP and ATP, induce the SDH activity provided by the SDH1 subunit. The regulation of SDH activity by adenine nucleotides is dependent on mitochondrial integrity and is prevented by atractyloside, an inhibitor of adenine nucleotide translocator (ANT), suggesting that the regulatory mechanism occurs on the mitochondrial matrix side of the inner mitochondrial membrane, and not in the intermembrane space, as previously suggested. On the other hand, in the intermembrane space, ADP and ATP limit mitochondrial oxygen consumption by a mechanism that appears to be related to cytochrome bc1 complex inhibition. Altogether, these results indicate that SA signaling and adenine nucleotides regulate the mitochondrial electron transport system and mitochondria-derived ROS production by direct effect in the electron transport system complexes, bringing new insights into mechanisms with direct implications in plant development and responses to different environmental responses, serving as a starting point for future physiological explorations.int for future physiological explorations.)
Hervouet 2005 Carcinogenesis + (Although mitochondrial deficiency in cance … Although mitochondrial deficiency in cancer has been described by Warburg, many years ago, the mechanisms underlying this impairment remain essentially unknown. Many types of cancer cells are concerned and, in particular, clear cell renal carcinoma (CCRC). In this cancer, the tumor suppressor gene, VHL (von Hippel-Lindau factor) is invalidated. Previous studies have shown that the transfection of the VHL gene in VHL-deficient cells originating from CCRCs could suppress their ability to form tumors when they were injected into nude mice. However, various additional genetic alterations are observed in such cancer cells. In order to investigate whether VHL invalidation was related to the mitochondrial impairment, we have studied the effects of wild-type VHL transfection into VHL-deficient 786-0 or RCC10 cells on their oxidative phosphorylation (OXPHOS) subunit contents and functions. We show that the presence of wild-type VHL protein (pVHL) increased mitochondrial DNA and respiratory chain protein contents and permitted the cells to rely on their mitochondrial ATP production to grow in the absence of glucose. In parallel to mtDNA increase, the presence of pVHL up regulated the mitochondrial transcription factor A, as shown by western blot analysis. In conclusion, in CCRCs, pVHL deficiency is one of the factors responsible for down-regulation of the biogenesis of OXPHOS complexes.ion of the biogenesis of OXPHOS complexes.)
Kukat 2014 PLoS Genet + (Although mitochondrial dysfunction is ofte … Although mitochondrial dysfunction is often accompanied by excessive reactive oxygen species (ROS) production, we previously showed that an increase in random somatic mtDNA mutations does not result in increased oxidative stress. Normal levels of ROS and oxidative stress could also be a result of an active compensatory mechanism such as a mild increase in proton leak. Uncoupling protein 2 (UCP2) was proposed to play such a role in many physiological situations. However, we show that upregulation of UCP2 in mtDNA mutator mice is not associated with altered proton leak kinetics or ROS production, challenging the current view on the role of UCP2 in energy metabolism. Instead, our results argue that high UCP2 levels allow better utilization of fatty acid oxidation resulting in a beneficial effect on mitochondrial function in heart, postponing systemic lactic acidosis and resulting in longer lifespan in these mice. This study proposes a novel mechanism for an adaptive response to mitochondrial cardiomyopathy that links changes in metabolism to amelioration of respiratory chain deficiency and longer lifespan.tory chain deficiency and longer lifespan.)
Karamercan 2013 Shock + (Although mitochondrial dysfunction is thou … Although mitochondrial dysfunction is thought to contribute to the development of posttraumatic organ failure, current techniques to assess mitochondrial function in tissues are invasive and clinically impractical. We hypothesized that mitochondrial function in peripheral blood mononuclear cells (PBMCs) would reflect cellular respiration in other organs during hemorrhagic shock and resuscitation.Using a fixed-pressure HS model, Long-Evans rats were bled to a mean arterial pressure of 40 mmHg. When blood pressure could no longer be sustained without intermittent fluid infusion (decompensated HS), lactated Ringer's solution was incrementally infused to maintain the mean arterial pressure at 40 mmHg until 40% of the shed blood volume was returned (severe HS). Animals were then resuscitated with 4× total shed volume in lactated Ringer's solution over 60 min (resuscitation). Control animals underwent the same surgical procedures, but were not hemorrhaged. Animals were randomized to control (''n'' = 6), decompensated HS (''n'' = 6), severe HS (''n'' = 6), or resuscitation (''n'' = 6) groups. Kidney, liver, and heart tissues as well as PBMCs were harvested from animals in each group to measure mitochondrial oxygen consumption using high-resolution respirometry. Flow cytometry was used to assess mitochondrial membrane potential (Ψm) in PBMCs. One-way analysis of variance and Pearson correlations were performed.Mitochondrial oxygen consumption decreased in all tissues, including PBMCs, following decompensated HS, severe HS, and resuscitation. However, the degree of impairment varied significantly across tissues during hemorrhagic shock and resuscitation. Of the tissues investigated, PBMC mitochondrial oxygen consumption and Ψm provided the closest correlation to kidney mitochondrial function during HS (complex I: ''r'' = 0.65; complex II: ''r'' = 0.65; complex IV: ''r'' = 0.52; ''P'' < 0.05). This association, however, disappeared with resuscitation. A weaker association between PBMC and heart mitochondrial function was observed, but no association was noted between PBMC and liver mitochondrial function.All tissues including PBMCs demonstrated significant mitochondrial dysfunction following hemorrhagic shock and resuscitation. Although PBMC and kidney mitochondrial function correlated well during hemorrhagic shock, the variability in mitochondrial response across tissues over the spectrum of hemorrhagic shock and resuscitation limits the usefulness of using PBMCs as a proxy for tissue-specific cellular respiration.oxy for tissue-specific cellular respiration.)
Wang 2011 Mol Oncol + (Although mitochondrial respiration is decr … Although mitochondrial respiration is decreased in most cancer cells, the role of this decrease in carcinogenesis and cancer progression is still unclear. To better understand this phenomenon, instead of further inhibiting mitochondrial function, we induced mitochondrial biogenesis in transformed cells by activating the peroxisome proliferator-activated receptors (PPARs)/peroxisome proliferator-activated receptor gamma co-activator 1α [[PGC-1alpha|(PGC-1α)]] pathways. This was achieved by treating the cells with bezafibrate, a PPARs panagonist that also enhances [[PGC-1α]] expression. We confirmed that bezafibrate treatment led to increased mitochondrial proteins and enzyme functions. We found that cells with increased mitochondrial biogenesis had decreased growth rates in glucose-containing medium. In addition, they became less invasive, which was directly linked to the reduced lactate levels. Surprisingly, even though bezafibrate-treated cells had higher levels of mitochondrial markers, total respiration was not significantly altered. However, respiratory coupling, and ATP levels were. Our data show that by increasing the efficiency of the mitochondrial oxidative phosphorylation system, cancer progression is hampered by decreases in cell proliferation and invasiveness.es in cell proliferation and invasiveness.)
Hickey 2009 Am J Physiol Cell Physiol + (Although most attention has been focused o … Although most attention has been focused on mitochondrial ATP production and transfer in failing hearts, less has been focused on the nonfailing hypertensive heart. Here, energetic complications are less obvious, yet they may provide insight into disease ontogeny. We studied hearts from 12-mo-old spontaneously hypertensive rats (SHR) relative to normotensive Wistar-Kyoto (WKY) rats. The ex vivo working-heart model of SHR showed reduced compliance and impaired responses to increasing preloads. High-resolution respirometry showed higher state 3 (with excess ADP) respiration in SHR left ventricle fibers with complex I substrates and maximal uncoupled respiration with complex I + complex II substrates. Respiration with ATP was depressed 15% in SHR fibers relative to WKY fibers, suggesting impaired ATP hydrolysis. This finding was consistent with a 50% depression of actomyosin ATPase activities. Superoxide production from SHR fibers was similar to that from WKY fibers respiring with ADP; however, it was increased by 15% with ATP. In addition, the apparent ''K''m for ADP was 54% higher for SHR fibers, and assays conducted after ''ex vivo'' work showed a 28% depression of complex I in SHR, but not WKY, fibers. Transmission electron microscopy showed similar mitochondrial volumes but a decrease in the number of cristae in SHR mitochondria. Tissue lipid peroxidation was also 15% greater in SHR left ventricle. Overall, these data suggest that although cardiac mitochondria from nonfailing SHR hearts function marginally better than those from WKY hearts, they show dysfunction after intense work. Impaired ATP turnover in hard-working SHR hearts may starve cardiac mitochondria of ADP and elevate superoxide.ve cardiac mitochondria of ADP and elevate superoxide.)
Dejean 2001 Biochim Biophys Acta + (Although on-line calorimetry has been wide … Although on-line calorimetry has been widely used to detect transitions in global metabolic activity during the growth of microorganisms, the relationships between oxygen consumption flux and heat production are poorly documented. In this work, we developed a respirometric and calorimetric approach to determine the enthalpy efficiency of respiration-linked energy transformation of isolated yeast mitochondria and yeast cells under growing and resting conditions. On isolated mitochondria, the analysis of different phosphorylating and non-phosphorylating steady states clearly showed that the simultaneous measurements of heat production and oxygen consumption rates can lead to the determination of both the enthalpy efficiency and the ATP/O yield of oxidative phosphorylation. However, these determinations were made possible only when the net enthalpy change associated with the phosphorylating system was different from zero. On whole yeast cells, it is shown that the simultaneous steady state measurements of the heat production and oxygen consumption rates allow the enthalpy growth efficiency (i.e. the amount of energy conserved as biomass compared to the energy utilised for complete catabolism plus anabolism) to be assessed. This method is based on the comparison between the calorimetric-respirometric ratio (CR ratio) determined under growth versus resting conditions during a purely aerobic metabolism. Therefore, in contrast to the enthalpy balance approach, this method does not rely on the exhaustive and tedious determinations of the metabolites and elemental composition of biomass. Thus, experiments can be performed in the presence of non-limiting amounts of carbon substrate, an approach which has been successfully applied to slow growing cells such as yeast cells expressing wild-type or a mutant rat uncoupling protein-1.type or a mutant rat uncoupling protein-1.)
Ali 2014 Abstract MiP2014 + (Although originally defined as harmful byp … Although originally defined as harmful byproducts of aerobic metabolism, reactive oxygen species (ROS) are currently believed to play a critical role in downstream signaling, which regulates protein kinases, phosphatases, transcription factors and ion transport channels. However, mechanisms by which ROS is responsively produced, sensed and translated in cellular domains, especially neurons, remain elusive. Recently, NADPH oxidase (NOX), which is a multimeric enzyme that catalyzes the production of superoxide (O2•) from O2 and NADPH and was originally identified in neutrophils as essential for the host response respiratory burst, has been shown to localize in the brain. The unexpected presence of NOX in neurons has led to the idea that NOX-induced ROS are important in non-host defense contexts; e.g. intracellular and intercellular redox signaling. In previous works, we showed that NOX is actively producing O2• in the brain and might therefore be an important element that influences redox homeostasis in health, disease, and aging. Questions on specific connections between NOX activation and neuronal dysfunctions remain open for exploration by unconventional experimental approaches capable of probing the implications of in vivo NOX assembly and activation. Here, we studied oxygen-consuming, superoxide-producing NOX basal as well as induced activities in synaptosomes. Isolated synaptosomes (severed nerve terminals) are studied because they contain all necessary components of a functional neuronal environment including ion channels, receptors, and mitochondria. We demonstrate the ability of the Oroboros Oxygraph-2k, in parallel with spin-trapping/labeling electron paramagnetic resonance (EPR) techniques, to study sources and dynamics of ROS in synaptosomes. To the best of our knowledge, this is the first time that the Oroboros system has been employed to quantify NOX activity in synaptosomes. to quantify NOX activity in synaptosomes.)
Maddalena 2017 Biochem Biophys Res Commun + (Although oxygen levels in the extracellula … Although oxygen levels in the extracellular space of most mammalian tissues are just a few percent, under standard cell culture conditions they are not regulated and are often substantially higher. Some cellular sources of reactive oxygen species, like NADPH oxidase 4, are sensitive to oxygen levels in the range between 'normal' physiological (typically 1-5%) and standard cell culture (up to 18%). Hydrogen peroxide in particular participates in signal transduction pathways via protein redox modifications, so the potential increase in its production under standard cell culture conditions is important to understand. We measured the rates of cellular hydrogen peroxide production in some common cell lines, including C2C12, PC-3, HeLa, SH-SY5Y, MCF-7, and mouse embryonic fibroblasts (MEFs) maintained at 18% or 5% oxygen. In all instances the rate of hydrogen peroxide production by these cells was significantly greater at 18% oxygen than at 5%. The increase in hydrogen peroxide production at higher oxygen levels was either abolished or substantially reduced by treatment with GKT 137831, a selective inhibitor of NADPH oxidase subunits 1 and 4. These data indicate that oxygen levels experienced by cells in culture influence hydrogen peroxide production via NADPH oxidase 1/4, highlighting the importance of regulating oxygen levels in culture near physiological values. However, we measured pericellular oxygen levels adjacent to cell monolayers under a variety of conditions and with different cell lines and found that, particularly when growing at 5% incubator oxygen levels, pericellular oxygen was often lower and variable. Together, these observations indicate the importance, and difficulty, of regulating oxygen levels experienced by cells in culture.en levels experienced by cells in culture.)
Ponce 2019 Thesis + (Although pathological alterations in gene … Although pathological alterations in gene expression and mitochondria function in response to cardiac ischemia are well recognized, the mechanisms driving these changes are incompletely understood. Nuclear to mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. Here we determine that cyclin C, a component of the transcriptional regulator, Mediator complex, directly regulates cardiac and mitochondrial function by modifying mitochondrial fission. We tested the hypothesis that cyclin C has a binary function as a transcriptional cofactor in the nucleus and acute regulation of cardiac energetics in ischemia by enhancing mitochondrial fission in the cytoplasm.In response to stress, cyclin C translocates to the cytoplasm enhancing mitochondria fission in part through interactions with Cdk1. Using cardiac specific cyclin C knockout and overexpression mouse models, we determined cyclin C regulates mitochondria morphology under basal and ischemic conditions ''in vivo''. Furthermore, pretreatment with a Cdk1 inhibitor followed by ischemia ''in vivo'' results in reduced mitochondrial fission. Together, our study reveals that cyclin C regulates both hypertrophic gene expression and mitochondrial fission providing new insights into the regulation of cardiac energy metabolism following acute ischemic injury.etabolism following acute ischemic injury.)
Chang 2016 Transl Res + (Although restoration of mitochondrial func … Although restoration of mitochondrial function in mitochondrial diseases through peptide-mediated allogeneic mitochondrial delivery (PMD) has been demonstrated ''in vitro'', the ''in vivo'' therapeutic efficacy of PMD in Parkinson's disease (PD) has yet to be determined. In this study, we compared the functionality of mitochondrial transfer with or without Pep-1 conjugation in neurotoxin (6-hydroxydopamine, 6-OHDA)-induced PC12 cells and PD rat models. We injected mitochondria into the medial forebrain bundle (MFB) of the PD rats after subjecting the nigrostriatal pathway to a unilateral 6-OHDA lesion for 21 days, and we verified the effectiveness of the mitochondrial graft in enhancing mitochondrial function in the soma of the substantia nigra (SN) neuron through mitochondrial transport dynamics in the nigrostriatal circuit. The result demonstrated that only PMD with allogeneic and xenogeneic sources significantly sustained mitochondrial function to resist the neurotoxin-induced oxidative stress and apoptotic death in the rat PC12 cells. The remaining cells exhibited a greater capability of neurite outgrowth. Furthermore, allogeneic and xenogeneic transplantation of peptide-labeled mitochondria after 3 months improved the locomotive activity in the PD rats. This increase was accompanied by a marked decrease in dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and consistent enhancement of tyrosine hydroxylase-positive immunoreaction of dopaminergic neurons in the SNc and striatum. We also observed that in the SN dopaminergic neuron in the treated PD rats, mitochondrial complex I protein and mitochondrial dynamics were restored, thus ameliorating the oxidative DNA damage. Moreover, we determined signal translocation of graft allogeneic mitochondria from the MFB to the calbindin-positive SN neuron, which demonstrated the regulatory role of mitochondrial transport in alleviating 6-OHDA-induced degeneration of dopaminergic neurons.Copyright © 2016 Elsevier Inc. All rights reserved. © 2016 Elsevier Inc. All rights reserved.)