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'''Authors:''' [[Axelrod Christopher L]] … '''Authors:''' [[Axelrod Christopher L]], [[Kirwan John P]] Obesity mediates the onset of lipid-induced insulin resistance, increasing the risk of type 2 diabetes. The inability of mitochondria to maintain core functions such as ATP synthesis, redox homeostasis, organelle quality control, and/or preservation of inheritance is proposed to link obesity-related insulin resistance to the onset and progression of type 2 diabetes, yet evidence remains elusive. To parse out the contributions of obesity versus peripheral insulin resistance, healthy weight adults were infused with an intralipid solution followed by evaluation of skeletal muscle mitochondrial function. The lipid infusion reduced insulin sensitivity and dampened mitochondrial membrane potential while increasing markers of mitochondrial fission and increasing the presence of autophagic vesicles, consistent with activation of the quality control machinery. Despite this, respiratory capacity and mitochondrial content were unaltered. From these studies, we concluded that activation of mitochondrial fission and quality control were early events in the onset of insulin resistance to defend cellular energy homeostasis. Subsequently, we conducted a cross-sectional analysis of individuals across the insulin sensitivity spectrum. We observed that markers of fission and quality control were markedly altered in patients with obesity and type 2 diabetes relative to obesity alone and healthy weight despite no apparent differences in respiratory capacity. Mitochondrial volume was incrementally lower in patients with obesity and type 2 diabetes relative to healthy weight. Collectively, we conclude that preservation of bioenergetic function in patients with obesity and type 2 diabetes is achieved by chronic activation of the quality control machinery which occurs at the expense of mitochondrial volume.y which occurs at the expense of mitochondrial volume. +
'''Authors:''' [[Barkova Daria]] … '''Authors:''' [[Barkova Daria]], [[Ukropec Jozef]], [[Nemec Michal]], [[Slobodova L]], [[Schoen M]], [[Tirpakova V]], [[Krumpolec P]], [[Sumbalova Zuzana]], [[Vician M]], [[Sedliak M]], [[Ukropcova Barbara]] '''Introduction:''' Regular exercise supports healthy ageing and reduces risk of elderly chronic diseases. Respirometry is an important tool in understanding the physiological adaptations in response to physical activity at cellular level. Previously, we showed that 3-month exercise training increases muscle metabolism in the elderly. Present study is aimed to assess the effects of long-term training on muscle oxidative capacity in the subset of individuals continuing regular training for 5 years. '''Methods:''' Volunteers (n=60, 66.9±1.2 years, 27.1±3.9 kg/m2) were recruited for 3-month intervention study: 36 of them underwent aerobic-strength training, 24 volunteers were active controls. A volunteer subpopulation continued aerobic-strength training for next 5 years (n=15), and is compared to non-exercising controls (n=15). Body composition, glucose tolerance, insulin sensitivity and other metabolic parameters were assessed. Samples of m. vastus lateralis obtained by biopsy were used for measurement of muscle mitochondria oxygen consumption by O2k high-resolution respirometry, applying RP1 SUIT protocol. '''Results and discussion:''' Three-month exercise training enhanced muscle mitochondrial respiration rate in the elderly undergoing exercise training compared to controls. So far, two individuals completed follow up phenotyping after 5 years training. A slight deterioration in anthropometric (increased BMI by ~ 8 % and visceral fat content by ~ 36%) and metabolic parameters was observed, together with a reduction in muscle mitochondrial respiration (by ~ 15 %). Short-term training improved the whole-body and muscle metabolism in the elderly. Obtaining data from exercising and non-exercising cohorts (currently ongoing) will allow us to assess the impact of a long-term intervention.ongoing) will allow us to assess the impact of a long-term intervention. +
'''Authors:''' [[Brunetta Henver Simionato]] … '''Authors:''' [[Brunetta Henver Simionato]], [[Palermo Ruiz Gabriel]], [[Ludwig Raissa]], [[Ruberti Olivia]], [[Bechara Luiz]], [[Consonni Silvio]], [[Rodrigues Bruno]], [[Ferreira Julio Cesar B]], [[Mori Marcelo AS]] The negative effects of high-fat high-sucrose (HFHS) diet consumption on heart function are exacerbated in mice lacking DICER in adipocytes (AdicerKO). These findings suggest a protective role of adipocyte-derived microRNAs on heart physiology. Exercise training is known to have a protective role in cardiometabolic diseases. However, it is not known whether chronic aerobic training is able to rescue heart dysfunction in HFHS-fed AdicerKO mice. Here, we fed AdicerKO mice with a HFHS diet for 12 weeks, after confirming the deleterious effects of the diet on these mice, we submitted them to moderate aerobic training for 8 weeks, 5 days/week for 60 minutes each section while keeping them on HFHS-diet. Chronic aerobic training restored end-systolic volume and stroke volume in the hearts of HFHS-fed AdicerKO mice without changing ejection fraction. In addition, aerobic exercise increased left ventricle diameter in both, systolic and diastolic, phases. Notably, HFHS-fed AdicerKO-trained mice presented lower heart rate with no differences in systolic blood pressure compared to HFHS-fed AdicerKO sedentary mice. Mechanistically, chronic exercise training lowered mitochondrial H2O2 emission and oxidative stress alongside greater lipid- and succinate-supported mitochondrial respiration. Importantly, these effects were not followed by changes in triacylglycerol content within the left ventricle or fibrosis. In summary, chronic aerobic training is capable to rescue heart function of HFHS-fed AdicerKO mice in association with improvements in mitochondrial bioenergetics and redox balance.ssociation with improvements in mitochondrial bioenergetics and redox balance. +
'''Authors:''' [[Cardoso Luiza HD]] … '''Authors:''' [[Cardoso Luiza HD]], [[Donnelly Chris]], [[Komlodi Timea]], [[Doerrier Carolina]], [[Gnaiger Erich]] '''Introduction:''' Multiple mt-matrix dehydrogenases reduce NAD+ to NADH+H+, which is oxidized by CI (N-junction). Convergent electron flow through several mt-Complexes (CI, CII, CETF, etc) reduces electron transfer system (ETS)-reactive ubiquinone (UQ) to ubiquinol (UQH2), which is oxidized by CIII (Q-junction). The aim of our study was to analyze the relationships between the N- and Q-redox states and electron transfer rates. '''Methods:''' Respiration and N- or Q-redox fractions were measured simultaneously with the Oroboros NextGen-O2k. Multiple protocols were used with sequential titrations of substrates, inhibitors, and uncouplers [1, 2]: N-pool with pyruvate&glutamate&malate, mouse liver mitochondria; Q-pool with succinate&rotenone, octanoylcarnitine&malate or palmitoylcarnitine&malate, permeabilized HEK 293T. After substrates, ADP, CCCP and antimycin A were titrated. '''Results and discussion:''' Varying energy supply upstream of the Q-junction by using combinations of substrates and ETS-inhibitors in the noncoupled state, the Q-pool became reduced in direct proportion to respiration. In contrast, varying downstream energy demand in the absence of ADP (LEAK), by ADP activation (OXPHOS), and by uncoupler titrations (ET capacity), the N- and Q-pools were reduced in indirect proportion to respiration. The opposite correlations between redox state and respiratory rate were explained by the contrasting effects of varying electron push from different fuel substrates of the ETS or electron pull modulated by coupling and corresponding energy demand. Special emphasis on the interaction between fatty acid oxidation, CI, and CII – all involving separate electron entries into the Q-junction [3] – is particularly relevant in the context of obesity and bioenergetics studies.# Komlódi T, Cardoso LHD, Doerrier C, Moore AL, Rich PR, Gnaiger E (2021) Coupling and pathway control of coenzyme Q redox state and respiration in isolated mitochondria. https://doi.org/10.26124/bec:2021-0003# Gnaiger E (2020) Mitochondrial pathways and respiratory control. An introduction to OXPHOS analysis. 5th ed. https://doi.org/10.26124/bec:2020-0002 # Gnaiger E (2023) Complex II ambiguities ― FADH2 in the electron transfer system. https://doi.org/10.26124/mitofit:2023-0003.v4 E (2023) Complex II ambiguities ― FADH2 in the electron transfer system. https://doi.org/10.26124/mitofit:2023-0003.v4 +
'''Authors:''' [[Chicco Adam J]] … '''Authors:''' [[Chicco Adam J]], [[Le Catherine H]], [[Mulligan Christopher M]], [[Whitcomb Luke A]], [[Evans Amanda E]], [[Routh Melissa A]], [[Sparanga Genevieve C]] Cardiolipin (CL) is a tetra-acyl mitochondrial phospholipid that supports the optimal function of several mitochondrial membrane proteins and processes. In the healthy mammalian heart, the majority of CL species contain four linoleate acyl chains (L4CL). A marked depletion of cardiac L4CL is paralleled by an increase in CL species containing docosahexaenoic acid (DHA) in hyperphagic obese (''Lepob''; OB) mice despite no change in dietary fat composition [1], but the mechanisms and functional relevance of these changes are unclear. We hypothesized that this shift in CL composition results from increased activity of delta-6 desaturase (D6D), the rate limiting enzyme in the biosynthesis of DHA and conversion of linoleate into highly unsaturated ω-6 fatty acids, by altering the distribution of fatty acids available for CL remodeling. To test this, we administered the selective D6D inhibitor SC-26196 (100 mg/kg/d in chow) to 4-5 month-old OB or lean (C57Bl/6) mice for 4 weeks. As hypothesized, D6D inhibition reversed obesity-related changes in cardiac CL composition, restoring L4CL and DHA-enriched CL species to within 5 % of levels in lean mice, which paralleled reciprocal shifts in the linoleate and DHA levels of total myocardial phospholipids. Obesity-related decreases in cardiac mitochondrial respiratory control by ADP (with NS pathway substrates) and greater mitochondrial H2O2 release during both LEAK and OXPHOS states were also abolished by D6D inhibition. These results corroborate accumulating evidence that cardiac CL composition is strongly influenced by the membrane fatty acids available for CL remodeling [2-3], and may impact the bioenergetic efficiency of mitochondrial respiration. # Han X, Yang J, Yang K, ZhongdancZ, Abendschein DR, Gross RW (2007) Alterations in Myocardial Cardiolipin Content and Composition Occur at the Very Earliest Stages of Diabetes: A Shotgun Lipidomics Study Biochemistry https://doi.org/10.1021/bi7004015 # Le CH et al. (2014) Delta-6-desaturase links PUFA metabolism with phospholipid remodeling and disease progression in heart failure. https://doi.org/10.1161/CIRCHEARTFAILURE.113.000744 # Oemer G, Edenhofer ML, Wohlfarter Y, Lackner K, Leman G, Koch J, Cardoso LHD, Lindner HH, Gnaiger E, Dubrac S, Zschocke J, Keller MA (2021) Fatty acyl availability modulates cardiolipin composition and alters mitochondrial function in HeLa cells. https://doi.org/10.1016/j.jlr.2021.100111 and alters mitochondrial function in HeLa cells. https://doi.org/10.1016/j.jlr.2021.100111 +
'''Authors:''' [[Giordano Luca]] … '''Authors:''' [[Giordano Luca]], [[Nolte A]], [[Wittig Ilka]], [[Pak Oleg]], [[Knoepp F]], [[Ramser K]], [[Wahl J]], [[Cabrera A]], [[Huettemann Maik]], [[Grossman Lawrence]], [[Pecina Petr]], [[Ghofrani HA]], [[Seeger W]], [[Weissmann Norbert]], [[Giehl K]], [[Sommer Natascha]] '''Introduction:''' Hypoxia in the lung alveoli triggers the contraction of the small precapillary pulmonary arteries, i.e., hypoxic pulmonary vasoconstriction (HPV), avoiding life-threatening hypoxemia. Pulmonary arterial smooth muscle cells (PASMCs) are involved in HPV, with the mitochondrial cytochrome c oxidase (COX) subunit 4 isoform 2 (Cox4i2) playing an essential role in the acute oxygen sensing1. Nonetheless, the molecular mechanism by which Cox4i2 sensitizes the whole COX remains unclear. '''Methods:''' We analysed superoxide production by MitoSOX, oxygen consumption by high-resolution respirometry, redox changes of the electron transport system (ETS) by RAMAN spectroscopy, and supercomplex formation by blue native gel analysis of PASMCs isolated from wild type (WT) and Cox4i2 knockout mice (Cox4i2 KO) exposed to normoxia or hypoxia. To figure out the role of Cox4i2-specific cysteine residues we generated mouse epithelial (CMT167) cells overexpressing either Cox4i1, or WT Cox4i2, or Cox4i2 mutants (C41S, C55A, C109S), and we tested their superoxide production and oxygen affinity. '''Results:''' Respiration, abundance, and COX assembly were similar in WT and Cox4i2 KO PASMCs. On the contrary, hypoxia-induced production of superoxide and the reduction of ETS components (NADH, ubiquinol, cytochrome c) was prevented in Cox4i2 KO PASMCs. CMT167 cells expressing either Cox4i1, or Cox4i2 mutants lacked hypoxia-induced superoxide production, which was detected only in cells expressing WT Cox4i2. Overexpression of Cox4i1, or Cox4i2, or Cox4i2 mutants did not affect oxygen affinity. Our findings suggests that Cox4i2 does not alter superoxide production by rearrangement of supercomplexes, but by the reduction of the ETS, likely mediated by the cysteine residues.Sommer N, Hüttemann M, et al. Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing. Circ Res. 2017;121(4):424-38.r Acute Pulmonary Oxygen Sensing. Circ Res. 2017;121(4):424-38. +
'''Authors:''' [[Guerrier Lisa]] … '''Authors:''' [[Guerrier Lisa]], [[Malpuech-Brugere C]], [[Bacoeur-Ouzillou O]], [[Cassagnes L]], [[Pezet D]], [[Gagniere J]], [[Richard R]], [[Touron Julianne]] '''Introduction:''' Adipose tissue (AT), as an endocrine organ, plays an important role in health and diseases, but unlike skeletal muscle, its energy metabolism have been under investigated due to technical limitations. Nevertheless, according to recent studies, mitochondria could play a predominant role in AT disorders and their activity could depend on adiposity level (1-3). This study aims to evaluate mitochondrial activity and metabolism of human visceral and subcutaneous white AT and their relationship with body mass index (BMI) and composition. '''Methods:''' Sixty-two patients undergoing digestive surgery, without chemotherapy, nor parietal infection, have been included in the study with BMI ranging from 15.4 to 51.9 kg·m-2. Their body composition was assessed by computed tomographic (CT) image at third lumbar vertebra (L3). Mitochondrial function was measured in situ in digitonin-permeabilized adipocytes using high resolution respirometry and a substrate/inhibitor titration approach (Figure) (4,5). Protein accumulation of mitochondrial and lipid metabolism key elements was evaluated by Western-blot. '''Results and discussion:''' Results showed a negative correlation between maximal mitochondrial respiration and BMI (p<0.05) as well as with AT surface, regardless of the anatomical location, though, OXPHOS respiration was significantly higher in visceral (2.22±0.15 pmol·sec-1·mg-1) than in the subcutaneous AT (1.79±0.17 pmol·sec-1·mg-1). Thus, mitochondrial function can be studied with small amount of AT despite its low mitochondrial density and can be discriminated according to AT depot and BMI. Further analyses are required to know whether the observed differences are quantitative and/or qualitative, as well as to identify the mechanisms involved # Ling Y et al. (2019) Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue. https://doi.org/10.1093/ajcn/nqz144# Fischer B, Schöttl T, Schempp C, Fromme T, Hauner H, Klingenspor M, Skurk T (2015) Inverse relationship between body mass index and mitochondrial oxidative phosphorylation capacity in human subcutaneous adipocytes. https://doi.org/10.1152/ajpendo.00524.2014# Wessels B, Honecker J, Schöttl T, Stecher L, Klingenspor M, Hauner H, Skurk T (2019) Adipose Mitochondrial Respiratory Capacity in Obesity is Impaired Independently of Glycemic Status of Tissue Donors. https://doi.org/10.1002/oby.22435# Kraunsøe R, Boushel R, Neigaard Hansen C, Schjerling P, Qvortrup K, Støckel M, Mikines KJ, Dela F (2010) Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity. https://doi.org/10.1113/jphysiol.2009.184754# Sahl RE, Frederikke Høy Helms E, Schmücker M, Flensted-Jensen M, Ingersen A, Morville T, Dela F, Wulff Helge J, Larsen S (2021) Reliability and variation in mitochondrial respiration in human adipose tissue. https://doi.org/10.1080/21623945.2021.1991617en S (2021) Reliability and variation in mitochondrial respiration in human adipose tissue. https://doi.org/10.1080/21623945.2021.1991617 +
'''Authors:''' [[Holloway Graham P]] … '''Authors:''' [[Holloway Graham P]], [[Petrick Heather L]], [[van Loon LJC]] Mitochondria play a key role in metabolic homeostasis, with impaired mitochondrial biology directly linked with numerous pathological conditions, including skeletal muscle atrophy, insulin resistance and heart dysfunction. Our team has focused on identifying nutritional approaches that preserve mitochondrial bioenergetics as a preventative medicine approach. In particular, we have studied dietary nitrate, which can be consumed through foods such as beets and green leafy vegetables or supplementation, as this compound appears to positively affect mitochondrial bioenergetics in diverse tissues. Additionally, we have shown that dietary nitrate can prevent high-fat diet-induced cardiac dysfunction, whole-body insulin resistance, dyslipidemia, and hepatic dysfunction. Moreover, we have recently uncovered that nitrate prevents skeletal muscle disuse-mediated reductions in mitochondrial protein synthesis rates (FSR), mitochondrial protein content, respiration and prevented the normal increase mitochondrial reactive oxygen species (ROS) emission during limb immobilization. While these physiological outcomes are likely in part linked to the serial reduction of nitrate to systemic nitric oxide (NO)-mediated vasodilation, we have also utilized fecal microbial transplantation from nitrate-fed donors to prevent HFD-induced cardiac dysfunction in the absence of increasing serum nitrate or reducing blood pressure. Given these systemic, reproducible, and consistent effects, nitrate appears to represent a viable therapeutic approach to improve mitochondrial bioenergetics to combat compromised cardiometabolic health in diverse situations.promised cardiometabolic health in diverse situations. +
'''Authors:''' [[Jasinska Joanna]] … '''Authors:''' [[Jasinska Joanna]], [[Bednarczyk Piotr]], [[Kalenik B]], [[Kulawiak Bogusz]], [[Wrzosek A]], [[Szewczyk Adam]] Recent studies point out that mitochondria are not only a source of ATP in the cell, but more and more data indicate their role related to Ca2+ buffering, production of reactive oxygen species (ROS) and activation of intracellular signaling pathways of necrosis and apoptosis. Recent studies clearly indicate that mitochondrial potassium channels (mitoK) present in the inner mitochondrial membrane play an important protective role in the ischemia-reperfusion processes of myocardial cell damage. These results were obtained using low molecular weight chemicals. Due to the lack of selective modulators of potassium channels, we opted for an alternative approach to modulate the activity of mitoK channels by changing the redox state of the respiratory chain, which we have demonstrated in previous studies. Some respiratory chain proteins are thought to absorb infrared (IR) light. Cytochrome c oxidase (COX) may be important in these mechanisms because it has four metal redox centers: binuclear CuA, CuB, heme a, and heme a3. All these metal centers are able to absorb light waves in the IR region. Data obtained in our laboratory indicate that COX may be functionally linked to mitochondrial high-conductance Ca2+-activated potassium channels (mitoBKCa) in the U87 cell line1. Using the patch-clamp technique with the illumination system, we exposed the mitoBKCa channel. We observed that in the presence of ferricyanide, channel activity was inhibited and that mitoBK channel activity could be restored by 820 nm illumination, suggesting that COX is involved in the modulation of mitoBK channel activity.# Szewczyk A and Bednarczyk P (2018) Modulation of the Mitochondrial Potassium Channel Activity by Infrared Light. https://doi.org/10.1016/j.bpj.2017.11.288ed Light. https://doi.org/10.1016/j.bpj.2017.11.288 +
'''Authors:''' [[Karabatsiakis Alexander]] … '''Authors:''' [[Karabatsiakis Alexander]], [[Manrique Juan-Salinas]], [[Stoll Thomas]], [[Hennessy Thomas]], [[Hill Michelle M]], [[Dietrich Detlef E]] Major depressive disorder (MDD) is characterized by impairments in mental and physical performance. Despite intensified hypothesis-driven research, applicable biomarkers for MDD are missing. Research showed that MD is associated with impaired mitochondrial bioenergetic functioning in peripheral blood mononuclear cells (PBMC). However, deeper biomolecular insights into bioenergetic and associated biochemical changes in blood underlying the pathophysiology of MDD are necessary to identify new biomarker candidates. Here, the biochemistry of PBMC-surrounding blood was analyzed using a hypothesis-free biomarker identification approach combining metabolite and lipid fingerprinting. Biochemical fingerprints of serum were compared between female individuals (N = 44) with and without MDD. Serum extracts were separated by liquid chromatography and detected with time-of-flight mass spectrometry. The data was analyzed by multiple group comparisons and correlations, as well as two multivariate classification procedures. Next, our previously identified alterations in mitochondrial bioenergetics in PBMC were co-considered as an outcome for our biomarker identification approach. Consequently, the most promising compound was tested for correlation with mitochondrial respiration. Nine biomarker candidates discriminated between MDD and non-MDD with high predictive accuracy (90.9 %). The detected compounds are involved in lipid and amino acid-metabolism. ''9,10-dihydroxy-octadenedioic acid'' was revealed as a robust biomarker candidate with a predictive accuracy of 81.8 % and significant mean positive correlation with parameters of mitochondrial respiration (r = 0.31-0.48, p<0.01). Our fingerprinting results highlight novel biomarker candidates and associated pathways for MDD research. The unraveled biochemical pathways indicate a modulated association of MDD with inflammation, oxidative stress, and mitochondrial bioenergetics. The biomarker candidates have to be replicated in independent cohorts of all ages & sexes.be replicated in independent cohorts of all ages & sexes. +
'''Authors:''' [[Kopecky Jan]] … '''Authors:''' [[Kopecky Jan]], [[Zouhar Petr]], [[Janovska Petra]], [[Bardova K]], [[Otahal J]], [[Vrbacky Marek]], [[Mracek Tomas]], [[Adamcova K]], [[Lenkova L]], [[Funda J]], [[Cajka T]], [[Drahota Zdenek]], [[Stanic S]], [[Rustan Arild C]], [[Horakova Olga]], [[Houstek Josef]], [[Rosmeissl M]] Heat production is essential for maintaining a constant body temperature, and is an important component of energy balance. Well-described mechanisms involved in heat generation include shivering of muscle and non-shivering thermogenesis (NST) in brown adipose tissue (BAT). Thermogenesis in BAT, which is dependent on the presence of the mitochondrial protein UCP1, is the focus of interest for its potential use in the treatment of obesity. Other mechanisms of NST and their significance are relatively poorly understood. We have shown [1] that obesity-resistant A/J mice acclimated to cold failed to increase adrenergically stimulated NST in BAT and activated NST in skeletal muscle instead. Heat generation in muscle involved increased calcium ion cycling in the endoplasmic reticulum associated with higher mitochondrial oxidative activity. The involvement of different thermogenic mechanisms could be related to the different susceptibility to obesity. The resistance of A/J mice to obesity may result, at least in part, from their ability to activate NST in muscle. Such mechanism may provide a more promising way to treat obesity than potential therapies based on increasing thermogenesis in BAT, as the capacity of skeletal muscle of adult human to burn fat energy stores is several fold greater than in BAT. Thus, only a relatively small increase in thermogenesis in muscle could significantly reduce adipose tissue deposition. How to achieve such an increase is a challenge for further research. # Janovska P et al., 2023, Mol Metab. https://doi.org/10.1016/j.molmet.2023.101683Metab. https://doi.org/10.1016/j.molmet.2023.101683 +
'''Authors:''' [[Mahapatra Gargi]] … '''Authors:''' [[Mahapatra Gargi]], [[Gao Zhengrong]], [[Bateman James R III]], [[Lockhart Samuel Neal]], [[Bergstrom Jaclyn]], [[Craft Suzanne]], [[Molina Anthony JA]] Impaired glucose tolerance (IGT), including prediabetes and diabetes, increases risk of developing age related disorders, including Alzheimer’s disease (AD). We analyzed mitochondrial bioenergetics in platelets collected from 208 adults, 55 years and older, with or without insulin sensitivities (112 normoglycemics (NG), 96 IGTs). Platelets from IGT participants exhibited unique bioenergetic profiles exemplified by higher mitochondrial respiration than NG. IGT platelets exhibited higher glucose-dependent maximal (Max) and spare respiratory (SRC) capacities compared to NG, and higher fatty acid oxidation-dependent maximal coupled (MaxOXPHOS) and uncoupled (MaxETS) respiration compared to NG. Correlating bioenergetics from all 208 participants combined with glucose measures (OGTT_120, OGTT_AUC, and HbA1c) revealed significant positive associations. Most associations were unaltered with age, sex, and BMI adjustments. Further separating NG and IGT participants and correlating platelet respiration with glucose measures revealed distinct trends in NG versus IGT group. In NG, previously observed associations remained intact, and new significant positive associations emerged between platelet bioenergetics and HbA1c. Associations in IGT group were overall negative. Identifying systemic mitochondrial mechanisms that associate with glucose intolerance in older adults will help in monitoring pathological progression of AD in relation to comorbidities such as insulin sensitivity, and supports the development of minimally invasive biomarkers of AD.# Mahapatra G, Gao, Bateman JR III, Lockhart SN, Bergstrom J, DeWitt AR, Piloso JE, Kramer PA, Gonzalez-Armenta JL, Amick A, Casanova R, Craft S, Molina AJA (2022) Blood-Based Bioenergetic Profiling Reveals Differences in Mitochondrial Function Associated with Cognitive Performance and Alzheimer’s Disease Alzheimer's & Dementia 2022. https://doi.org/10.1002/alz.12731 & Dementia 2022. https://doi.org/10.1002/alz.12731 +
'''Authors:''' [[Nagwani Amit K]] … '''Authors:''' [[Nagwani Amit K]], [[Kaczmarek L]], [[Kmita H]] '''Introduction:''' Tardigrades are considered as one of the toughest animals on Earth due to their remarkable ability to withstand extreme condition. An example of these conditions is hypomagnetic field (HMF, static magnetic field with an intensity <5 μT), which is known to influence the metabolic processes including mitochondria functioning. However, very few studies considering HMF impact were performed for organisms able to survive under extreme conditions and considered as suitable for outer space colonization. Therefore, we decided to check the impact of HMF on the tardigrade ''Paramacrobiotus experimentalis'' focusing on mitochondria functionality reflected by the mitochondrial inner membrane potential (ΔΨ) having regard to age and sex. '''Methods:''' Females and males from 3 different age classes (i.e., 30-60, 150-180 and >300 days) were extracted from laboratory culture and divided into experimental and control groups exposed to HMF and standard magnetic field (SMF), respectively, for three different durations i.e., 7 days, 15 days and 30 days. The HMF treatment was performed in a special anti-magnetic chamber whereas SMF treatment was performed in a climate chamber. TMRM staining of intact animals was used to estimate ΔΨ. '''Results and discussion:''' The calculated FITMRM index indicated HMF-related changes in Δψ dependent on age and sex. Accordingly, HMF effect was most pronounced for the oldest animals and males appeared to be more sensitive to HMF than females that correlated with the survival rate. The results provide an insight into mechanisms of HMF effect that could be useful for organization of space travels and living outside the Earth. # Mo W, Liu Y, He R. (2014) Hypomagnetic field, an ignorable environmental factor in space? https://doi.org/10.1007/s11427-014-4662-x# Binhi VN, Prato FS (2017) Biological effects of the hypomagnetic field: An analytical review of experiments and theories. https://doi.org/10.1371/journal.pone.0179340# Conley CC (1970) A Review of the biological effects of very low magnetic fields. NASA. Technical Note; TN D-5902: 1–27. https://ntrs.nasa.gov/citations/19700024915# Erdmann W, Idzikowski B, Kowalski W, Kosicki J, Kaczmarek Ł (2021) Tolerance of two anhydrobiotic tardigrades Echiniscus testudo and Milnesium inceptum to hypomagnetic conditions. https://doi.org/10.7717/peerj.10630scus testudo and Milnesium inceptum to hypomagnetic conditions. https://doi.org/10.7717/peerj.10630 +
'''Authors:''' [[Owesny Patricia]] … '''Authors:''' [[Owesny Patricia]], [[Hegemann N]], [[Kuebler WM]], [[Ost Mario]], [[Grune T]], [[Ott C]] Cardiac aging is a multifactorial process, which is associated with increased oxidative stress, cell death and mitochondrial abnormalities. These factors can lead to an overall impairment of cardiac function and substrate utilization [1,2]. With the increased prevalence of obesity and related comorbidities, especially coronary heart disease, it was proposed that obesity could present a condition of premature heart aging [3]. Therefore, our aim is to compare the impact of obesity and aging on heart function, as well as the cardiac energy metabolism, focusing on mitochondria. Our experimental design of diet-induced obesity contains three different age groups (22, 76 and 106 weeks), where male C57BL/6J mice receive either a High fat/High-carb or a Standard diet for 8 weeks. After dietary intervention, mice underwent echocardiographic or metabolic treadmill analysis. Heart tissue was used for the Oroboros O2k measurement of mitochondrial bioenergetics. In further studies of cardiac energy metabolism Western blot and qPCR in heart tissue and isolated cardiomyocytes were performed. Echocardiography revealed a decline in cardiac output in mice 76 and 106 weeks of age with a further decrease by High fat/High-carb diet. Interestingly, these effects were more pronounced in 76 weeks group. In the same group we investigated indications of an impaired mitochondrial energy metabolism, specifically associated with cardiomyocytes. Although, loss of cardiac function with age has been previously described, we demonstrate here a key role for mitochondrial energy metabolism in this loss of function. # Houtkooper R H, Argmann C, Houten S M, Cantó C, Jeninga E H, Andreux P A, Thomas C, Doenlen R, Schoonjans K, Auwerx J (2011), The metabolic footprint of aging in mice. https://doi.org/10.1038/srep00134. # Lazzeroni D, Villatore A, Souryal G, Pili G, Peretto G (2022), The Aging Heart: A Molecular and Clinical Challenge. https://doi.org/10.3390/ijms232416033.# Ren J, Dong F, Cai G-J, Zhao P, Nunn J M, Wold L E, Pei J (2010), Interaction between age and obesity on cardiomyocyte contractile function: role of leptin and stress signaling. https://doi.org/10.1371/journal.pone.0010085.n and stress signaling. https://doi.org/10.1371/journal.pone.0010085. +
'''Authors:''' [[Petrick Heather L]] … '''Authors:''' [[Petrick Heather L]], [[Aussieker T]], [[Fuchs CJ]], [[Hermans WJ]], [[Betz MW]], [[Pinckaers PJM]], [[Snijders T]], [[van Loon LJC]], [[Holloway Graham P]] '''Introduction:''' Mitochondrial ADP sensitivity represents an important control point in oxidative phosphorylation. The sensitivity of mitochondria to ADP is lower in high-lipid environments, in aging males, and in young females compared to young males. However, the interaction between sex, age, and body composition (fat mass) in the regulation of mitochondrial ADP sensitivity remains unknown. '''Methods:''' Vastus lateralis muscle biopsies were obtained from healthy, recreationally active, young males (n=21, 24±4 y, 22.7±2.2 kg/m2 BMI), young females (n=20, 21±2 y, 21.7±2.2 kg/m2), older males (n=13, 76±5 y, 25.8±2.5 kg/m2), and older females (n=6, 70±6 y, 23.4±3.0 kg/m2). Permeabilized fibers were prepared to measure mitochondrial ADP sensitivity. Whole-body DEXA scans were performed. Data (mean±SD) were analyzed using two-way ANOVAs. '''Results and discussion:''' Body fat percentage was higher in females and older individuals (main effects). While maximal mitochondrial respiration did not differ between groups, mitochondrial ADP sensitivity was affected by sex and age. Specifically, in younger individuals mitochondrial ADP sensitivity was lower in females compared with males (~15 % higher apparent ADP Km, p=0.02). Older males also showed ~15% lower mitochondrial ADP sensitivity compared with young males (p=0.04). In contrast to young individuals, mitochondrial ADP sensitivity was numerically greater (~15 %) in older females when compared with older males (p=0.14) and younger females (p=0.12). However, there were no correlations between body fat percentage and mitochondrial apparent ADP Km in any group. We speculate that sex-based differences in mitochondrial ADP sensitivity are impacted by estrogen as opposed to body composition, as this response is lost with aging. ADP sensitivity are impacted by estrogen as opposed to body composition, as this response is lost with aging. +
'''Authors:''' [[Phang Howard J]] … '''Authors:''' [[Phang Howard J]], [[Gerwick W]], [[Molina Anthony JA]] Mitochondrial bioenergetic decline is a well known biological hallmark of aging, suggesting that mitochondria-targeting therapeutics have great potential in treating age-related diseases and conditions [1]. Despite this, their efficacy within the context of human aging remains largely unknown. We sought to develop a phenotypic screening platform to identify agents that directly modulate mitochondrial function in human cells. Marine natural products (MNP) represent a large, under-explored chemical space with immense therapeutic potential [2]. We screened a MNP library of 125 pure compounds at 10, 1, and 0.1 µg/mL incubated for 24 hours with with primary human dermal fibroblasts (pHDF) as summarized in Figure 1. We leveraged the San Diego Nathan Shock Center which houses 50+ pHDF lines derived from healthy donors across a spectrum of adult age. Cultured pHDF retain age-related phenotypes including mitochondrial bioenergetic decline, which presents a robust opportunity to identify bioenergetic effects within the context of human aging [3]. Thus, we used pHDF from a donor representative of an “older” phenotype (74 years of age) to ensure aging relevance. We identified numerous compounds that modulate mitochondrial function in a dose-dependent manner. Our primary outcomes were change in basal or maximal respiration using high throughput respirometry (Agilent Seahorse XFe96). This screening platform successfully identified compounds with stimulatory as well as inhibitory effects on respiratory capacity. Future steps include further validation of hit compounds using high-resolution respirometry on the Oroboros O2k. These studies will elucidate mechanistic effects on the electron transfer system as well as effects on cells of different donor ages. # Murphy MP, Hartley RC (2018) Mitochondria as a therapeutic target for common pathologies. https://doi.org/10.1038/nrd.2018.174.# Liang X, Luo D, Luesch H (2018) Advances in exploring the therapeutic potential of marine natural products. https://doi.org/10.1016/j.phrs.2019.104373. # Auburger G, Klinkenberg M, Drost J, Marcus K, Morales-Gordo B, Kunz WS, Brandt U, Broccoli V, Reichmann H, Gispert S, Jendrach M (2012). Primary Skin Fibroblasts as a Model of Parkinson's Disease. https://doi.org/10.1007/s12035-012-8245-1. Parkinson's Disease. https://doi.org/10.1007/s12035-012-8245-1. +
'''Authors:''' [[Piel Sarah]] … '''Authors:''' [[Piel Sarah]], [[cManus Meagan J]], [[Heye K]], [[Beaulieu F]], [[Fazeliniae H]], [[Janowska Joanna I]], [[McTurk B]], [[Starr Jonathan]], [[Gaudio H]], [[Patel N]], [[Hefti MM]], [[Smalley M]], [[Hook JF]], [[Kohli NV]], [[Bruton J]], [[Hallowell T]], [[Delso N]], [[Roberts A]], [[Lin Y]], [[Ehinger Johannes K]], [[Karlsson Michael]], [[Berg RA]], [[Morgan RW]], [[Kilbaugh Todd J]] '''Introduction:''' Despite advancements in cardiopulmonary resuscitation (CPR), secondary neurological injury remains the key determinant of successful recovery from cardiac arrest (CA) [1-3]. Currently, there are no established clinical therapies that preserve neurological function [4]. We previously found that acute decline in mitochondrial health up to 24 hours post-CA correlated with poor neurological outcome [5-6]. Here, we tested the potential of dimethyl fumarate (DMF), a derivative of the TCA-cycle intermediate fumaric acid shown to enhance mitochondrial bioenergetics [7], to improve mitochondrial injury in brain and heart following successful resuscitation after CA. '''Methods:''' Female piglets representing toddler age underwent asphyxia, followed by ventricular fibrillation, cardiopulmonary resuscitation and defibrillation until return of spontaneous circulation. Subsequently, animals received daily treatment with DMF or vehicle. Sham animals underwent identical anesthesia protocols and instrumentation without CA. After 4 days, animals (n=5 of each group) were euthanized, tissues were harvested and their mitochondrial function, quantity and proteomic profile was analyzed. '''Results and discussion:''' Mitochondrial content and function, as measured by citrate synthase activity and high-resolution respirometry, was reduced at 4 days following CA. In contrast, myocardial mitochondria demonstrated a complete restoration of mitochondrial content and function despite persistent changes in mitochondrial ultrastructure. DMF treatment prevented 25 % of the long-term proteomic changes in the brain, including proteins related to mitochondrial bioenergetics and oxidative stress. In addition, myocardial mitochondrial morphology was normalized by DMF. In this model of CA, mitochondria sustained persistent damage in an organ-specific manner. DMF partially prevents these long-term mitochondrial changes in myocardium and brain.# Berg RA et al: Incidence and Outcomes of Cardiopulmonary Resuscitation in PICUs. Crit Care Med 2016; 44(4):798-808# Slomine BS, Silverstein FS, Christensen JR, et al: Neurobehavioural outcomes in children after In-Hospital cardiac arrest. Resuscitation 2018; 124:80-89# Laver S, Farrow C, Turner D, et al: Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004; 30(11):2126-2128# Neumar RW et al: Post-Cardiac Arrest Syndrome. Circulation 2008; 118(23):2452-2483# Lautz AJ, Morgan RW, Karlsson M, et al: Hemodynamic-Directed Cardiopulmonary Resuscitation Improves Neurologic Outcomes and Mitochondrial Function in the Heart and Brain. Critical care medicine 2019; 47(3):e241-e249# Kilbaugh TJ, Sutton RM, Karlsson M, et al: Persistently Altered Brain Mitochondrial Bioenergetics After Apparently Successful Resuscitation From Cardiac Arrest. Journal of the American Heart Association 2015; 4(9):e002232# Hayashi G, Jasoliya M, Sahdeo S, et al: Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Human molecular genetics 2017; 26(15):2864-2873ice and humans. Human molecular genetics 2017; 26(15):2864-2873 +
'''Authors:''' [[Pytlak Karolina]] … '''Authors:''' [[Pytlak Karolina]], [[Maliszewska – Olejniczak K]], [[Sek Aleksandra]], [[Szewczyk Adam]], [[Bednarczyk Piotr]], [[Kulawiak Bogusz]] Human bronchial epithelial (HBE) cells form an external barrier in the airways and are constantly exposed to factors such as urban dust. Recently, the large conductance calcium-activated potassium (mitoBKCa) channel has been identified in the inner mitochondrial membrane of HBE cells. The pore-forming subunit of the channel is encoded by the ''KCNMA1'' gene, which also encodes plasma membrane BKCa channels. Mitochondrial potassium channels regulate mitochondrial membrane potential, oxygen consumption, mitochondrial volume and reactive oxygen species synthesis. Activation of mitoBKCa induces cytoprotection of cardiac and brain tissue. In our project, we applied CRISPR/Cas9 technique to disrupt ''KCNMA1'' gene in the HBE cell line (16HBE14o- cells). The newly formed line showed no mitoBKCa channel activity. We also noticed changes related to the deregulation of the cell cycle. The loss of mitoBKCa significantly affected mitochondrial function. We observed a decrease in the rate of mitochondrial respiration. Furthermore, we analyzed the organization of respiratory chain complexes using Blue Native electrophoresis. In addition, analysis of the expression of selected genes encoding mitochondrial proteins showed changes in cells with disrupted ''KCNMA1'' gene. Nevertheless, a thorough understanding of the observed mitochondrial dysfunction requires further study.We conclude that the presence of the mitoBKCa channel in HBE cells is essential for the preservation of mitochondrial function and is important for the proper function of these cells as part of the human airways. for the preservation of mitochondrial function and is important for the proper function of these cells as part of the human airways. +
'''Authors:''' [[Sadler Daniel]] … '''Authors:''' [[Sadler Daniel]], [[Treas L]], [[Ross T]], [[Sikes JD]], [[Britton SL]], [[Koch LG]], [[Borsheim Elisabet]], [[Porter Craig]] '''Introduction:''' Low cardiorespiratory fitness (CRF) is associated with a greater risk for metabolic disease. The potential for early life exercise training to overcome metabolic perturbations imparted by low intrinsic CRF remains unknown. We tested the hypothesis that early life exercise training would overcome whole-body and tissue metabolic defects imparted by low CRF.'''Methods:''' At 26 days of age, rat low-capacity runners (LCR, ''n''=20) and high-capacity runners (HCR, ''n''=20) generated by artificial selection were assigned to either sedentary control (CTRL, n=10) or voluntary wheel running (VWR, ''n''=10) for 6 weeks. Post-intervention, whole-body metabolic phenotyping was performed, and the respiratory function of isolated skeletal muscle and liver mitochondria assayed. Quantitative proteomics were performed on tissue samples.'''Results and discussion:''' HCR-VWR performed 1.8-fold greater volume of wheel running than LCR-VWR (P<0.001). In LCR, VWR reduced body fat (''P''<0.001), increased total daily energy expenditure (+16 %, ''P''=0.030), and enhanced glucose tolerance (''P''=0.040). Muscle mitochondrial respiratory function was unaffected by VWR in both strains, although VWR increased muscle mitochondrial protein content (both ''P''<0.05). VWR enhanced the respiratory capacity of HCR hepatic mitochondria (+23 %, ''P''=0.040). Proteomic analyses revealed lower capacity for fatty acid oxidation in muscle and liver of LCR-CTRL versus HCR-CTRL, which was not rescued by VWR. VWR reduced hepatic pyruvate kinase abundance in both strains (both ''P''<0.013), indicating VWR may shift fuel preferences of hepatic mitochondria. These results reveal early life exercise training partially overcomes the metabolic phenotype imparted by low intrinsic CRF, although proteomic adaptations to early exercise training remain influenced by intrinsic CRF. to early exercise training remain influenced by intrinsic CRF. +
'''Authors:''' [[Saleem Ranim]] … '''Authors:''' [[Saleem Ranim]], [[Scott Graham R]] '''Introduction:''' High-altitude environments are characterized by cold temperatures and low O2 levels (hypoxia). Small mammals at high altitude thus face the metabolic challenge of maintaining thermogenesis to cope with cold in a hypoxic environment that can constrain aerobic ATP supply. Circulatory O2 delivery by the heart is essential for supporting tissue O2 demands, but it is unclear whether evolved or plastic changes in cardiac mitochondria help overcome constraints on thermogenesis in high-altitude environments. '''Method:''' We examined this issue in deer mice (Peromyscus maniculatus). Mice from populations native to high altitude and low altitude were born and raised in captivity, and adults were acclimated to warm (25 °C) normoxia or cold (5 °C) hypoxia (~12 kPa O2 for 5-6 weeks) in a full-factorial design. Mitochondrial function was studied by high-resolution respirometry and fluorometry in permeabilized tissue from left ventricles and was complemented by assays of several metabolic and antioxidant enzymes. '''Results and discussion:''' Mitochondrial capacities for oxidative phosphorylation and electron transport were similar between populations and were unaffected by acclimation to cold hypoxia, as were activities of citrate synthase and cytochrome oxidase. However, exposure to cold hypoxia increased activities of lactate dehydrogenase, which were also greater in highlanders than in lowlanders, likely to augment capacities for lactate oxidation. Furthermore, mitochondrial emission of reactive oxygen species was lower in highlanders than in lowlanders across environments, associated with lower levels of lipid peroxidation and protein carbonyls. Therefore, phenotypic plasticity and evolved changes in cardiac mitochondria help deer mice cope with metabolic challenges at high altitude. evolved changes in cardiac mitochondria help deer mice cope with metabolic challenges at high altitude. +