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De Carvalho 2017 Toxicol Research + (''Eugenia uniflora'' L(Myrtaceae family) h … ''Eugenia uniflora'' L(Myrtaceae family) has demonstrated several properties of human interest, including insecticide potential, due to its pro-oxidant properties. These properties likely result from the effects on its mitochondria, but the mechanism of this action is unclear. The aim of this work was to evaluate the mitochondrial bioenergetics function in ''Drosophila melanogaster'' exposed to ''E. uniflora'' leaf essential oil. For this, we used a high-resolution respirometry (HRR) protocol. We found that ''E. uniflora'' promoted a collapse of the mitochondrial transmembrane potential (ΔΨm). In addition the essential oil was able to promote the disruption of respiration coupled to oxidative phosphorylation (OXPHOS) and inhibit the respiratory electron transfer-pathway (ET-pathway) established with an uncoupler. In addition, exposure led to decreases of respiratory control ratio (RCR), bioenergetics capacity and OXPHOS coupling efficiency, and induced changes in the substrate control ratio. Altogether, our results suggested that ''E. uniflora'' impairs the mitochondrial function/viability and promotes the uncoupling of OXPHOS, which appears to play an important role in the cellular bioenergetics failure induced by essential oil in ''D. melanogaster''.d by essential oil in ''D. melanogaster''.)
Schatz 2011 Feuersucher + (''From'' [http://www.annualreviews.org/doi … ''From'' [http://www.annualreviews.org/doi/pdf/10.1146/annurev-biochem-081009-125448 Schatz G (2012) The fires of life. Annu Rev Biochem 81: 34–59.]:This retrospective recounts the hunt for the mechanism of mitochondrialATP synthesis, the early days of research on mitochondrial formation,and some of the colorful personalities dominating these oftendramatic and emotional efforts. The narrative is set against the backdropof postwar Austria and Germany and the stream of young scientistswho had to leave their countries to receive postdoctoral trainingabroad. Many of them—including the author—chose the laboratory ofa scientist their country had expelled a few decades before. The articleconcludes with some thoughts on the uniqueness of U.S. research universitiesand a brief account of the struggles to revive science in Europe.Illustriert von P. Leslie Dutton Europe. Illustriert von P. Leslie Dutton)
Gordillo 2015 Can J Microbiol + (''Geotrichum citri-aurantii'' is a posthar … ''Geotrichum citri-aurantii'' is a postharvest phytopathogenic fungus of lemons. We studied the mode of action of antifungal metabolites from ''Bacillus sp.'' strain IBA 33 on arthroconidia of ''G. citri-aurantii''. These metabolites are lipopeptides belonging to the iturin family. Membrane permeabilization of ''G. citri-aurantii'' was analyzed and mitochondrial respiratory rate was evaluated. Disturbance of the plasma membrane promotes the leakage of many cellular components into the surrounding media, and mitochondrial membrane disorganization promotes the inhibition of the respiratory rate. Our findings provide insights into the ability of lipopeptides to suppress plant fungal pathogens and their possible agronomical applications.d their possible agronomical applications.)
Mastronicola 2011 IUBMB Life + (''Giardia intestinalis'' is the microaerop … ''Giardia intestinalis'' is the microaerophilic protozoon causing giardiasis, a common infectious intestinal disease. ''Giardia'' possesses an O2 -scavenging activity likely essential for survival in the host. We report that Giardia trophozoites express the O2 -detoxifying flavodiiron protein (FDP), detected by immunoblotting, and are able to reduce O2 to H2O rapidly (∼3 μM O2 × min × 106 cells at 37 °C) and with high affinity (C50 = 3.4 ± 0.7 μM O2). Following a short-term (minutes) exposure to H2O2 ≥ 100 μM, the O2 consumption by the parasites is irreversibly impaired, and the FDP undergoes a degradation, prevented by the proteasome-inhibitor MG132. Instead, H2O2 does not cause degradation or inactivation of the isolated FDP. On the basis of the elevated susceptibility of ''Giardia'' to oxidative stress, we hypothesize that the parasite preferentially colonizes the small intestine since, compared with colon, it is characterized by a greater capacity for redox buffering and a lower propensity to oxidative stress.e that the parasite preferentially colonizes the small intestine since, compared with colon, it is characterized by a greater capacity for redox buffering and a lower propensity to oxidative stress.)
Mendoza-Fuentes 2023 PeerJ + (''Heterotheca inuloides'', traditionally e … ''Heterotheca inuloides'', traditionally employed in Mexico, has demonstrated anticancer activities. Although it has been proven that the cytotoxic effect is attributed to cadinane-type sesquiterpenes such as 7-hydroxy-3,4-dihydrocadalene, the mechanism of action by which these agents act in tumor lines and their regulation remain unknown. This study was undertaken to investigate for first time the cytotoxic activity and mechanism of action of 7-hydroxy-3,4-dihydrocadalene and two semi-synthetic cadinanes derivatives towards breast cancer cells.Cell viability and proliferation were assayed by thiazolyl blue tetrazolium bromide (MTT) assay and Trypan blue dye exclusion assay. Cell migration measure was tested by wound-healing assay. Moreover, the reactive oxygen species (ROS) and lipid peroxidation generation were measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay and thiobarbituric acid reactive substance (TBARS) assay, respectively. Furthermore, expression of caspase-3, Bcl-2 and GAPDH were analyzed by western blot.The results showed that 7-hydroxy-3,4-dihydrocadalene inhibited MCF7 cell viability in a concentration and time dependent manner. The cytotoxic potency of semisynthetic derivatives 7-(phenylcarbamate)-3,4-dihydrocadalene and 7-(phenylcarbamate)-cadalene was remarkably lower. Moreover, ''in silico'' studies showed that 7-hydroxy-3,4-dihydrocadalene, and not so the semi-synthetic derivatives, has optimal physical-chemical properties to lead a promising cytotoxic agent. Further examination on the action mechanism of 7-hydroxy-3,4-dihydrocadalene suggested that this natural product exerted cytotoxicity via oxidative stress as evidenced in a significantly increase of intracellular ROS levels and in an induction of lipid peroxidation. Furthermore, the compound increased caspase-3 and caspase-9 activities and slightly inhibited Bcl-2 levels. Interestingly, it also reduced mitochondrial ATP synthesis and induced mitochondrial uncoupling.Taken together, 7-hydroxy-3,4-dihydrocadalene is a promising cytotoxic compound against breast cancer via oxidative stress-induction.ast cancer via oxidative stress-induction.)
Harari 2015 Vintage + (''Homo deus'' shows us where we're going. … ''Homo deus'' shows us where we're going. Yuval Harari envisions a near future in sihch we face a new set of challenges. ''Homo deus'' exlores the projects, dreams and nightmares that will shape the twendty-first century and beyond - from overcoming death to creating artificial life. It asks the fundamental questions: how can we protect this fragile world from our own desctructive power? And what does our future hold?tive power? And what does our future hold?)
McMurray 2019 FASEB J + (''In utero'' overnutrition can predispose … ''In utero'' overnutrition can predispose offspring to metabolic disease. Although the mechanisms are unclear, increased oxidative stress accelerating cellular aging has been shown to play a role. Mitochondria are the main site of reactive oxygen species (ROS) production in most cell types. Levels of ROS and the risk for oxidative damage are dictated by the balance between ROS production and antioxidant defense mechanisms. Originally considered as toxic species, physiologic levels of ROS are now known to be essential cell signaling molecules. Using a model of maternal overnutrition in C57BL6N mice, we investigate the mechanisms involved in the development of insulin resistance (IR) in muscle. In red and white gastrocnemius muscles of offspring, we are the first to report characteristics of oxidative phosphorylation, H2O2 production, activity of mitoflashes, and electron transport chain supercomplex formation. Results demonstrate altered mitochondrial function with reduced response to glucose in offspring of mice fed a high-fat and high-sucrose diet, increases in mitochondrial leak respiration, and a reduction in ROS production in red gastrocnemius in response to palmitoyl carnitine. We also demonstrate differences in supercomplex formation between red and white gastrocnemius, which may be integral to fiber-type specialization. We conclude that in this model of maternal overnutrition, mitochondrial alterations occur before the development of IR.ion, mitochondrial alterations occur before the development of IR.)
Holt 1988 Nature + (''In vitro'' studies of muscle mitochondri … ''In vitro'' studies of muscle mitochondrial metabolism in patients with mitochondrial myopathy have identified a variety of functional defects of the mitochondrial respiratory chain, predominantly affecting complex I (NADH-CoQ reductase) or complex III (ubiquinol-cytochrome c reductase) in adult cases. These two enzymes consist of approximately 36 subunits, eight of which are encoded by mitochondrial DNA (mtDNA). The increased incidence of maternal, as opposed to paternal, transmission in familial mitochondrial myopathy suggests that these disorders may be caused by mutations of mtDNA. Multiple restriction endonuclease analysis of leukocyte mtDNA from patients with the disease, and their relatives, showed no differences in cleavage patterns between affected and unaffected individuals in any single maternal line. When muscle mtDNA was studied, nine of 25 patients were found to have two populations of muscle mtDNA, one of which had deletions of up to 7 kilobases in length. These observations demonstrate that mtDNA heteroplasmy can occur in man and that human disease may be associated with defects of the mitochondrial genome. with defects of the mitochondrial genome.)
JanssenDuijghuijsen 2017 Front Physiol + (''In vivo'' studies suggest that intestina … ''In vivo'' studies suggest that intestinal barrier integrity is dependent on mitochondrial ATP production. Here, we aim to provide mechanistic support, using an ''in vitro'' model mimicking the oxidative ''in vivo'' situation.Human Caco-2 cells were cultured for 10 days in culture flasks orfor 14 days on transwell inserts in either glucose-containing or galactose-containingmedium. Mitochondria were visualized and cellular respiration and levels of oxidativephosphorylation (OXPHOS) proteins were determined. Mitochondrial ATP depletionwas induced using CCCP, rotenone, or piericidin A (PA). Monolayer permeability wasassessed using transepithelial electrical resistance (TEER) and fluorescein flux. Geneexpression and cellular distribution of tight junction proteins were analyzed.Caco-2 cells cultured in galactose-containing, but not in glucose-containing,medium showed increased mitochondrial connectivity, oxygen consumption rates andlevels of OXPHOS proteins. Inhibition of mitochondrial ATP production using CCCP,rotenone or PA resulted in a dose-dependent increase in Caco-2 monolayer permeability.In-depth studies with PA showed a six fold decrease in cellular ATP and revealedincreased gene expression of tight junction proteins (TJP) 1 and 2, occludin, and claudin1, but decreased gene expression of claudin 2 and 7. Of these, claudin 7 was clearlyredistributed from the cellular membrane into the cytoplasm, while the others were not(TJP1, occludin) or slightly (claudin 2, actin) affected. ''In vivo'' studies suggest that intestinal barrier integrity is dependent on mitochondrial ATP production. Here, we aim to providemechanistic support, using an ''in vitro'' model mimicking the oxidative ''in vivo'' situation.Well-functioning mitochondria are essential for maintaining cellularenergy status and monolayer integrity of galactose grown Caco-2 cells. Energydepletion-induced Caco-2 monolayer permeability may be facilitated by changes in thedistribution of claudin 7. changes in the distribution of claudin 7.)
Wagner 1998 Plant Physiol + (''In vivo'' ubiquinone (UQ) reduction leve … ''In vivo'' ubiquinone (UQ) reduction levels were measured during the development of the inflorescences of ''Arum maculatum'' and ''Amorphophallus krausei''. Thermogenesis in ''A. maculatum'' spadices appeared not to be confined to a single developmental stage, but occurred during various stages. The UQ pool in both ''A. maculatum'' and ''A. krausei'' appendices was approximately 90% reduced during thermogenesis. Respiratory characteristics of isolated appendix mitochondria did not change in the period around thermogenesis. Apparently, synthesis of the required enzyme capacity is regulated via a coarse control upon which a fine control of metabolism that regulates the onset of thermogenesis is imposed.tes the onset of thermogenesis is imposed.)

(''In vivo'' ubiquinone (UQ) reduction levels were measured during the de)

Rocco-Machado 2019 Free Radic Biol Med + (''Leishmania amazonensis'' is one of leish … ''Leishmania amazonensis'' is one of leishmaniasis' causative agents, a disease that has no cure and leads to the appearance of cutaneous lesions. Recently, our group showed that heme activates a Na+/K+ ATPase in these parasites through a signaling cascade involving hydrogen peroxide (H2O2) generation. Heme has a pro-oxidant activity and signaling capacity, but the mechanism by which this molecule increases H2O2 levels in ''L. amazonensis'' has not been elucidated. Here we investigated the source of H2O2 stimulated by heme, ruling out the participation of mitochondria and raising the possibility of a role for a NADPH oxidase (Nox) activity. Despite the absence of a classical Nox sequence in trypanosomatid genomes, ''L. amazonensis'' expresses a surface ferric iron reductase (LFR1). Interestingly, Nox enzymes are thought to have evolved from ferric iron reductases because they share same core domain and are very similar in structure. The main difference is that Nox catalyses electron flow from NADPH to oxygen, generating reactive oxygen species (ROS), while ferric iron reductase promotes electron flow to ferric iron, generating ferrous iron. Using ''L. amazonensis'' overexpressing or knockout for LFR1 and heterologous expression of LFR1 in mammalian embryonic kidney (HEK 293) cells, we show that this enzyme is bifunctional, being able to generate both ferrous iron and H2O2. It was previously described that protozoans knockout for LFR1 have their differentiation to virulent forms (amastigote and metacyclic promastigote) impaired. In this work, we observed that LFR1 overexpression stimulates protozoan differentiation to amastigote forms, reinforcing the importance of this enzyme in ''L. amazonensis'' life cycle regulation. Thus, we not only identified a new source of ROS production in Leishmania, but also described, for the first time, an enzyme with both ferric iron reductase and Nox activities.Copyright © 2019 Elsevier Inc. All rights reserved.o described, for the first time, an enzyme with both ferric iron reductase and Nox activities. Copyright © 2019 Elsevier Inc. All rights reserved.)
Pinho 2020 PLoS Negl Trop Dis + (''Leishmania'' species are responsible for … ''Leishmania'' species are responsible for a broad spectrum of diseases, denominated Leishmaniasis, affecting over 12 million people worldwide. During the last decade, there have been impressive efforts for sequencing the genome of most of the pathogenic ''Leishmania'' spp. as well as hundreds of strains, but large-scale proteomics analyses did not follow these achievements and the ''Leishmania'' proteome remained mostly uncharacterized. Here, we report a comprehensive comparative study of the proteomes of strains representing ''L. braziliensis'', ''L. panamensis'' and ''L. guyanensis'' species. Proteins extracted by SDS-mediated lysis were processed following the multi-enzyme digestion-filter aided sample preparation (FASP) procedure and analysed by high accuracy mass spectrometry. "Total Protein Approach" and "Proteomic Ruler" were applied for absolute quantification of proteins. Principal component analysis demonstrated very high reproducibility among biological replicates and a very clear differentiation of the three species. Our dataset comprises near 7000 proteins, representing the most complete ''Leishmania'' proteome yet known, and provides a comprehensive quantitative picture of the proteomes of the three species in terms of protein concentration and copy numbers. Analysis of the abundance of proteins from the major energy metabolic processes allow us to highlight remarkably differences among the species and suggest that these parasites depend on distinct energy substrates to obtain ATP. Whereas ''L. braziliensis'' relies the more on glycolysis, ''L. panamensis'' and ''L. guyanensis'' seem to depend mainly on mitochondrial respiration. These results were confirmed by biochemical assays showing opposite profiles for glucose uptake and O2 consumption in these species. In addition, we provide quantitative data about different membrane proteins, transporters, and lipids, all of which contribute for significant species-specific differences and provide rich substrate for explore new molecules for diagnosing purposes. Data are available via ProteomeXchange with identifier PXD017696.ailable via ProteomeXchange with identifier PXD017696.)
MitoCom2014 + (''MitoCom'' closing event and perspectives. Innsbruck, Austria; 2014 October 16)
Barsottini 2020 Commun Biol + (''Moniliophthora perniciosa'' is a fungal … ''Moniliophthora perniciosa'' is a fungal pathogen and causal agent of the witches' broom disease of cocoa, a threat to the chocolate industry and to the economic and social security in cocoa-planting countries. The membrane-bound enzyme alternative oxidase (MpAOX) is crucial for pathogen survival; however a lack of information on the biochemical properties of MpAOX hinders the development of novel fungicides. In this study, we purified and characterised recombinant MpAOX in dose-response assays with activators and inhibitors, followed by a kinetic characterization both in an aqueous environment and in physiologically-relevant proteoliposomes. We present structure-activity relationships of AOX inhibitors such as colletochlorin B and analogues which, aided by an MpAOX structural model, indicates key residues for protein-inhibitor interaction. We also discuss the importance of the correct hydrophobic environment for MpAOX enzymatic activity. We envisage that such results will guide the future development of AOX-targeting antifungal agents against ''M. perniciosa'', an important outcome for the chocolate industry.ortant outcome for the chocolate industry.)
Yurre 2020 Arq Bras Cardiol + (''Moringa oleifera'' seeds, which are used … ''Moringa oleifera'' seeds, which are used for water clarification, contain a lectin named WSMoL which has shown ''in vitro'' antibacterial and immunomodulatory activity. Due to their nutritional value and therapeutic potential, the leaves and seeds of this tree are eaten in some communities. Some plant lectins are non-toxic to mammals, but others have been reported to be harmful when ingested or administered by other means. As one of the steps needed to define the safety of WSMoL, we evaluated possible cardiotoxic effects of this purified protein. WSMoL was administered for 21 consecutive days to mice by gavage. Electrophysiological, mechanical, and metabolic cardiac functions were investigated by ''in vivo'' and ''ex vivo'' electrocardiographic recordings, nuclear magnetic resonance, and high-resolution respirometry. The treatment with WSMoL did not induce changes in blood glucose levels or body weight in comparison with control group. Moreover, the heart weight/body weight and heart weight/tibia length ratios were similar in both groups. Lectin ingestion also did not modify glucose tolerance or insulin resistance. No alterations were observed in electrocardiographic parameters or cardiac action potential duration. The heart of mice from the control and WSMoL groups showed preserved left ventricular function. Furthermore, WSMoL did not induce changes in mitochondrial function (in all cases, p > 0.05). The administration of WSMoL demonstrated a cardiac safety profile. These results contribute to the safety evaluation of using ''M. oleifera'' seeds to treat water, since this lectin is present in the preparation employed by some populations to this end.ion employed by some populations to this end.)
Pelaez Coyotl 2020 Pharmaceutics + (''Mycobacterium tuberculosis'' (MTB) is th … ''Mycobacterium tuberculosis'' (MTB) is the principal cause of human tuberculosis (TB), which is a serious health problem worldwide. The development of innovative therapeutic modalities to treat TB is mainly due to the emergence of multi drug resistant (MDR) TB. Autophagy is a cell-host defense process. Previous studies have reported that autophagy-activating agents eliminate intracellular MDR MTB. Thus, combining a direct antibiotic activity against circulating bacteria with autophagy activation to eliminate bacteria residing inside cells could treat MDR TB. We show that the synthetic peptide, IP-1 (KFLNRFWHWLQLKPGQPMY), induced autophagy in HEK293T cells and macrophages at a low dose (10 μM), while increasing the dose (50 μM) induced cell death; IP-1 induced the secretion of TNFα in macrophages and killed Mtb at a dose where macrophages are not killed by IP-1. Moreover, IP-1 showed significant therapeutic activity in a mice model of progressive pulmonary TB. In terms of the mechanism of action, IP-1 sequesters ATP ''in vitro'' and inside living cells. Thus, IP-1 is the first antimicrobial peptide that eliminates MDR MTB infection by combining four activities: reducing ATP levels, bactericidal activity, autophagy activation, and TNFα secretion. autophagy activation, and TNFα secretion.)
Iqbal 2018 Pathogens + (''Mycobacterium tuberculosis'' (Mtb) exhib … ''Mycobacterium tuberculosis'' (Mtb) exhibits remarkable metabolic flexibility that enables it to survive a plethora of host environments during its life cycle. With the advent of bedaquiline for treatment of multidrug-resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of Mtb on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. This includes targeting NADH dehydrogenase by phenothiazine derivatives, menaquinone biosynthesis by DG70 and other compounds, terminal oxidase by imidazopyridine amides and ATP synthase by diarylquinolines. Importantly, oxidative phosphorylation also plays a critical role in the survival of persisters. Thus, inhibitors of oxidative phosphorylation can synergize with frontline TB drugs to shorten the course of treatment. In this review, we discuss the oxidative phosphorylation pathway and development of its inhibitors in detail.d development of its inhibitors in detail.)
Franco 2020 bioRxiv + (''Mycobacterium tuberculosis'' (Mtb) regul … ''Mycobacterium tuberculosis'' (Mtb) regulates the macrophage metabolic state to thrive in the host. Yet, the responsible mechanisms remain elusive. Macrophage activation towards the microbicidal (M1) program depends on the HIF-1 α-mediated metabolic shift from oxidative phosphorylation towards glycolysis. Here, we asked whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We exposed M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PE), and found lower glycolytic activity, accompanied by elevated levels of oxidative phosphorylation and bacillary load, compared to controls. The host-derived lipid fraction of TB-PE drove these metabolic alterations. HIF-1α stabilization reverted the effect of TB-PE by restoring M1 metabolism. As a proof-of-concept, Mtb-infected mice with stabilized HIF-1α displayed lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages. Collectively, we demonstrate that host-derived lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection.hereby impairing control of Mtb infection.)
Baines 2020 Biochim Biophys Acta Bioenerg + (''No abstract available'')
Coen 2013 Obesity (Silver Spring) + (''OBJECTIVE'': The link between a reduced … ''OBJECTIVE'': The link between a reduced capacity for skeletal muscle mitochondrial fatty acid oxidation (FAO) and lipotoxicity in human insulin resistance has been the subject of intense debate. The objective of this study was to investigate whether reduced FAO is associated with elevated acyl CoA, ceramide, and diacylglycerol (DAG) in severely obese insulin resistant subjects.''DESIGN AND METHODS'': Muscle biopsies were conducted in lean (L, 22.6 ± 0.5 kg/m2, ''n'' = 8), Class I (CI, 32.1 ± 0.4 kg/m2, ''n'' = 7) and Class II&III obese (CII&III, 45.6 ± 1.1 kg/m2, ''n'' = 15) women for acyl CoA, sphingolipid and DAG profiling. Intramyocellular triglyceride (IMTG) content was determined by histology. FAO was assessed by incubating muscle homogenates with [1-C]palmitate and measuring CO2 production. Cardiolipin content was quantified as an index of mitochondrial content. Lipid metabolism proteins, DGAT1, PLIN5, and PNPLA2 were quantified in biopsy samples by western blot.''RESULTS'': CII&III were more insulin resistant (HOMA-IR: 4.5 ± 0.5 vs. 1.1 ± 0.1, ''P'' < 0.001), and had lower FAO (∼58%, ''P'' = 0.007) and cardiolipin content (∼31%, ''P'' = 0.013) compared to L. IMTG was elevated in CI (''P'' = 0.04) and CII&III (''P'' = 0.04) compared to L. Sphingolipid content was higher in CII&III compared to L (13.6 ± 1.1 vs. 10.3 ± 0.5 pmol/mg, ''P'' = 0.031) whereas DAG content was not different among groups. DGAT1 was elevated in CII&III, and PLIN5 was elevated in CI compared to L.''CONCLUSION'': Severe obesity is associated with reduced muscle oxidative capacity and occurs concomitantly with elevated IMTG, ceramide and insulin resistance.rs concomitantly with elevated IMTG, ceramide and insulin resistance.)