Dynamics of enhanced mitochondrial respiration in female compared with male rat cerebral arteries

Mitochondrial respiration has never been directly examined in intact cerebral arteries. We tested the hypothesis that mitochondrial energetics of large cerebral arteries ex vivo are sex dependent. The Seahorse XFe24 analyzer was used to examine mitochondrial respiration in isolated cerebral arteries from adult male and female Sprague-Dawley rats. We examined the role of nitric oxide (NO) on mitochondrial respiration under basal conditions, using Nω-nitro-l-arginine methyl ester, and following pharmacological challenge using diazoxide (DZ), and also determined levels of mitochondrial and nonmitochondrial proteins using Western blot, and vascular diameter responses to DZ. The components of mitochondrial respiration including basal respiration, ATP production, proton leak, maximal respiration, and spare respiratory capacity were elevated in females compared with males, but increased in both male and female arteries in the presence of the NOS inhibitor. Although acute DZ treatment had little effect on mitochondrial respiration of male arteries, it decreased the respiration in female arteries. Levels of mitochondrial proteins in Complexes I–V and the voltage-dependent anion channel protein were elevated in female compared with male cerebral arteries. The DZ-induced vasodilation was greater in females than in males. Our findings show that substantial sex differences in mitochondrial respiratory dynamics exist in large cerebral arteries and may provide the mechanistic basis for observations that the female cerebral vasculature is more adaptable after injury.

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Rat diaphragm mitochondria have lower intrinsic respiratory rates than mitochondria in limb muscles

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00203.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. R1311-R1315 ◽

Cited By ~ 3

Author(s):

Mary L. Garcia-Cazarin ◽

Jorge L. Gamboa ◽

Francisco H. Andrade

Keyword(s):

Aerobic Capacity ◽

Mitochondrial Respiration ◽

Anion Channel ◽

Activity Level ◽

Triceps Surae ◽

Sprague Dawley ◽

Voltage Dependent Anion Channel ◽

Mitochondrial Content ◽

Complex Iv ◽

Respiratory Complexes

The mitochondrial content of skeletal muscles is proportional to activity level, with the assumption that intrinsic mitochondrial function is the same in all muscles. This may not hold true for all muscles. For example, the diaphragm is a constantly active muscle; it is possible that its mitochondria are intrinsically different compared with other muscles. This study tested the hypothesis that mitochondrial respiration rates are greater in the diaphragm compared with triceps surae (TS, a limb muscle). We isolated mitochondria from diaphragm and TS of adult male Sprague Dawley rats. Mitochondrial respiration was measured by polarography. The contents of respiratory complexes, uncoupling proteins 1, 2, and 3 (UCP1, UCP2, and UCP3), and voltage-dependent anion channel 1 (VDAC1) were determined by immunoblotting. Complex IV activity was measured by spectrophotometry. Mitochondrial respiration states 3 (substrate and ADP driven) and 5 (uncoupled) were 27 ± 8% and 24 ± 10%, respectively, lower in diaphragm than in TS ( P < 0.05 for both comparisons). However, the contents of respiratory complexes III, IV, and V, UCP1, and VDAC1 were higher in diaphragm mitochondria (23 ± 6, 30 ± 8, 25 ± 8, 36 ± 15, and 18 ± 8% respectively, P ≤ 0.04 for all comparisons). Complex IV activity was 64 ± 16% higher in diaphragm mitochondria ( P ≤ 0.01). Mitochondrial UCP2 and UCP3 content and complex I activity were not different between TS and diaphragm. These data indicate that diaphragm mitochondria respire at lower rates, despite a higher content of respiratory complexes. The results invalidate our initial hypothesis and indicate that mitochondrial content is not the only determinant of aerobic capacity in the diaphragm. We propose that UCP1 and VDAC1 play a role in regulating diaphragm aerobic capacity.

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Curcumae Radix Extract Reduces Beta-Amyloid (Αβ) and Tau Protein Through Increased Mitochondrial Respiration

10.21203/rs.3.rs-785607/v1 ◽

2021 ◽

Author(s):

Seong lae Jo ◽

Hyun Yang ◽

Jun H. Heo ◽

Sang R. Lee ◽

Hye Won Lee ◽

...

Keyword(s):

Brain Tumor ◽

Energy Metabolism ◽

Neurodegenerative Diseases ◽

Mitochondrial Respiration ◽

Metabolic Flux ◽

Tca Cycle ◽

Basal Respiration ◽

Atp Production ◽

Inflammatory Conditions ◽

Brain Tumor Cells

Abstract Background: Neurodegenerative diseases are increasingly being studied owing to the increasing proportion of the aging population. Several potential compounds have been studied to prevent neurodegenerative diseases, one of which is Curcumae Radix that is known to be beneficial for inflammatory conditions, metabolic syndrome, and various types of pain. However, it is not well studied and its influence on energy metabolism in neurodegenerative diseases is unclear. We focused on the relationship between neurodegenerative diseases and energy metabolism through Curcumae Radix extract in an animal model. Methods: Mice were treated with Curcumae Radix extract for 5 weeks orally 5 times in a week (50 mg/kg body weight). Murine delayed brain tumor (DBT) cells were supplemented with Curcumae Radix extract. We monitored the neurodegenerative makers and metabolic indicators using Western blotting and qRT-PCR and then assessed the cellular glycolysis and mitochondrial respiration through metabolic flux assay.Results: Low expression levels of Alzheimer’s disease-related markers were observed after treatment with Curcumae Radix extract. It was determined through the pAMPK/AMPK ratio that the ATP state was sufficient in the cerebrum and brain tumor cells. With this, an increase in glycolysis would be expected as glucose is the main energy source of the brain. However, glycolysis-related genes and the extracellular acidification rate showed that glycolysis decreased. Despite this, basal respiration and ATP production through mitochondrial respiration and increased TCA cycle and OXPHOS-related genes were observed in the Curcumae Radix group. Conclusions: In neurodegenerative diseases involving mitochondrial dysfunction, Curcumae Radix may act as a metabolic modulator of brain health to treat and prevent these diseases.

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Abstract 15585: Sex Dimorphism in Prostaglandins’ Role in Thromboxane-dependent Contraction in the Rat Middle Cerebral Artery

Circulation ◽

10.1161/circ.142.suppl_3.15585 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Victor M Pulgar ◽

Ibrahim Elsaangeedy ◽

Liliya M Yamaleyeva

Keyword(s):

Ex Vivo ◽

Cerebral Arteries ◽

Cerebrovascular Reactivity ◽

Maximal Response ◽

Hormonal Changes ◽

Sprague Dawley ◽

Maximal Contraction ◽

Response Curves ◽

Sprague Dawley Rats ◽

Pre Treatment

Introduction: Recent evidences suggest that sex and estrogen can influence cerebrovascular reactivity. We investigated the role of prostanoids and the estrogen receptor (ER) ex vivo in isolated middle cerebral arteries from male (M-MCA) and female (F-MCA) rats. Methods: MCA segments isolated from 20-week-old male and female Sprague-Dawley rats were mounted on a wire Multi Myograph (DMT) to measure isometric tone. Acetylcholine (ACh) was used to assess endothelium integrity. Concentration response curves to the thromboxane analog U46619 (U4, 10 -11 -10 -5 M) were performed in arteries intact or pre-treated with indomethacin (I,10 -5 M) or the ER antagonist G15 (G, 10 -6 M). Data were acquired with Powerlab 8 (ADInstruments) and recorded with LabChart v8 (ADInstruments). Response to K + was expressed in mN/mm whereas U4 maximal contraction as percent of maximal response to 75mM K + (%K MAX ) and sensitivity as pD 2 (-LogEC 50 ). Results: M-MCA (n=10) and F-MCA (n=13) displayed similar optimal diameters (M vs. F; 214±12 vs. 218±5 μm, p>0.05) and ACh-dependent relaxation (M vs. F; 71±11 vs. 78±10 % pre-constricted tone; 7.3±0.4 vs. 7.2±0.2, p>0.05). A greater contraction to K + was observed in M-MCA (M vs. F; 1±0.2 vs. 0.6±0.1 mN/mm, p<0.05). M- and F-MCA showed similar maximal contraction (M vs. F; 116±6 vs. 109±10 %K MAX ) and sensitivity (M vs. F; 7.2±0.2 vs. 7.3±0.2) to U4. Pre-incubation with Indomethacin lowered maximal response and sensitivity (M vs. M-I; 116±6 vs. 97±5%K MAX, p<0.05; 7.2±0.2 vs. 6.8±0.1, p<0.05) to U4 in M-MCA, with no effect on F-MCA (F vs. F-I; 109±9 vs. 113±7%K MAX ; 7.3±0.2 vs. 7.3±0.2). Pre-treatment with G15 increased U4 sensitivity in M-MCA (M vs. M-G; 7.3±0.2 vs. 7.8±0.2, p<0.05), with no effect in F-MCA (F vs. F-G; 7.3±0.2 vs. 7.4±0.3). Conclusions: Our data demonstrate sex differences in thromboxane-dependent contraction of MCA in middle-aged rats. Hormonal changes during the estrous cycle may contribute to a greater variability of F-MCA responses.

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Abstract 383: 17 beta-Estradiol Enhances Mitochondrial Function of Cerebral Arteries From Ovariectomized Female Rats

Circulation Research ◽

10.1161/res.117.suppl_1.383 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Ibolya Rutkai ◽

Somhrita Dutta ◽

Korey A Walter ◽

Prasad V Katakam ◽

David W Busija

Keyword(s):

Mitochondrial Function ◽

Mitochondrial Respiration ◽

Cerebral Arteries ◽

Mitochondrial Protein ◽

Indirect Evidence ◽

Estradiol Level ◽

Female Rats ◽

Serum Estradiol ◽

Voltage Dependent Anion Channel ◽

Serum Estradiol Level

Previous studies have provided indirect evidence that circulating sex hormones alter the function of the cerebral circulation perhaps via effects on mitochondrial dynamics. However, effects of estrogen on mitochondrial respiration have never been directly examined. We have previously observed a difference in the mitochondrial function of cerebral arteries from male and female rats but the exact mechanisms are not clear. We tested the hypothesis that mitochondrial respiration in isolated cerebral arteries from ovariectomized (OVX) Sprague Dawley rats treated with a 21 d release, 0.5 mg of 17 β-estradiol pellet (OVX+E) was enhanced compared with arteries from placebo treated OVX rats. The Seahorse Bioscience XFe24 system was used to measure mitochondrial oxygen consumption rate (pM/min/μg protein) in cerebral arteries. Western blot was used to investigate the arterial expression of proteins. Radioimmunoassay was used to measure serum estradiol level. Treatment with 17 β-estradiol resulted in a higher serum estradiol level (146.9±18.16 pg/ml) and uterus weight (0.15±0.0058 g) in the OVX+E compared with the OVX (14.7±1.2 pg/ml, 0.07±0.003, respectively; p<0.05). The components of mitochondrial respiration in pM/min/μg protein including basal respiration (147±9), ATP production (44±4), proton leak (102±7), and maximal respiration (212±13) were elevated in OVX+E compared with OVX (105±13, 21±4, 50±6, 138±10, respectively; p<0.05). Expression of the mitochondrial DNA encoded Complexes I and III, the nuclear DNA encoded Complexes II, IV, V, and the voltage-dependent anion channel protein were similar in all groups. However, the ratios of phosphorylated endothelial and neuronal nitric oxide (NO) synthase normalized to total protein were significantly (p<0.05) elevated in the OVX+E (1.43±0.06, 1.15±0.2, respectively) compared with OVX group (0.92±0.06, 0.53±0.19, respectively). Our findings provide direct evidence for sex-specific differences in mitochondrial function on freshly isolated cerebral arteries. Thus, estradiol replacement enhances the efficacy of the oxidative phosphorylation resulting in an increased mitochondrial respiration which is not due to increased mitochondrial protein expression but may be due to enhanced NO.

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Cellular acidosis triggers MondoA transcriptional activity by driving mitochondrial ATP production

10.1101/376368 ◽

2018 ◽

Author(s):

Blake R. Wilde ◽

Zhizhou Ye ◽

Donald E. Ayer

Keyword(s):

Transcriptional Activity ◽

Adenine Nucleotide ◽

Cellular Stress ◽

Anion Channel ◽

Glycolytic Flux ◽

Voltage Dependent Anion Channel ◽

Interacting Protein ◽

Atp Production ◽

Stress Signals ◽

Regulatory Loop

ABSTRACTMondoA and its transcriptional target thioredoxin-interacting protein (TXNIP) constitute a regulatory loop that senses glycolytic flux and controls glucose availability. Cellular stress also triggers MondoA activity and TXNIP expression. To understand how MondoA integrates glucose and stress signals, we studied its activation by acidosis. We found that acidosis drives mitochondrial ATP (mtATP) synthesis. The subsequent export of mtATP from mitochondria via adenine-nucleotide transporter and voltage-dependent anion channel, and the enzymatic activity of mitochondria-bound hexokinase results in the production of glucose-6-phosphate (G6P), a known activator of MondoA transcriptional activity. MondoA localizes to the outer-mitochondrial membrane (OMM), and in response to G6P, shuttles to the nucleus and activates transcription. Our data suggests that MondoA is a required feature of a glucose- and mtATP-dependent, OMM-localized signaling center. We propose MondoA functions as a coincidence detector and its ability to sense glucose and cellular stress is coupled to the concerted production of G6P.

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The Role of Dietary Saturated Fat in Associations between Exposure to Ambient Fine Particulate Matter and Mitochondrial Respiratory Functions in Circulating Platelets

Current Developments in Nutrition ◽

10.1093/cdn/nzab041_038 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 523-523

Author(s):

Wan Shen ◽

Hao Chen ◽

James Samet ◽

Haiyan Tong

Keyword(s):

Oxygen Consumption ◽

Mitochondrial Respiration ◽

Saturated Fatty Acids ◽

Fine Particulate Matter ◽

Saturated Fat ◽

Basal Respiration ◽

Mitochondrial Oxygen Consumption ◽

Atp Production ◽

Consumption Rates ◽

Mitochondrial Respiratory

Abstract Objectives Exposure to ambient fine particulate matter (PM2.5) is associated with platelet activation and increased mitochondrial respiration. The impact of dietary saturated fat on the circulating platelets is not understood. This project aimed to determine whether dietary saturated fatty acids moderate mitochondrial respiratory function in circulating platelets after short-term exposure to PM2.5. Methods Platelets were isolated from 22 healthy male volunteers (mean age ± SD, 37 ± 8.2) in a panel study and measured for mitochondrial oxygen consumption rates using an extracellular flux analyzer. Intakes of saturated fat were determined from 24 hr dietary recalls the day before the assay. Daily ambient PM2.5 concentrations during the study period were obtained from ambient air quality monitoring stations. Data were fitted with a moderation model, where the level of ambient PM2.5 was the independent variable, saturated fat intake was the moderator, and mitochondrial respiratory functions in circulating platelets were the dependent variables. Results After controlling for age, dietary consumption of saturated fat moderated the mitochondrial oxygen consumption rates of non-mitochondrial respiration, basal respiration, maximum respiration, ATP production, and spare respiratory capacity after exposure to ambient PM2.5 with 2 days lag. Specifically, the negative associations between the above mentioned mitochondrial respiratory measurements and PM2.5 levels reached statistical significance (95% Confident Intervals did not include 0) in subjects with a high intake of total saturated fat. Further, results for individual saturated fatty acid showed similar patterns, specifically that negative association between mitochondrial oxygen consumption rates of non-mitochondrial respiration, basal respiration and ATP production and levels of exposed PM2.5 was moderated by intakes of short-chain (C4:0), medium-chain (C6:0, C8:0, C10:0, C12:0), long-chain (C14:0, C16:0) saturated fatty acids. Conclusions Taken together, these preliminary findings suggest that consumption of saturated fat moderates platelet mitochondrial respiration after exposure to PM2.5. THIS ABSTRACT OF A PROPOSED PRESENTATION DOES NOT NECESSARILY REFLECT EPA POLICY. Funding Sources This project was supported by the U.S. EPA Intramural Research Program.

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Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells

Cells ◽

10.3390/cells9010222 ◽

2020 ◽

Vol 9 (1) ◽

pp. 222 ◽

Cited By ~ 9

Author(s):

Andrey V. Kuznetsov ◽

Sabzali Javadov ◽

Michael Grimm ◽

Raimund Margreiter ◽

Michael J. Ausserlechner ◽

...

Keyword(s):

Energy Metabolism ◽

Fundamental Problem ◽

Anion Channel ◽

Cardiac Cells ◽

Cytoskeletal Proteins ◽

Voltage Dependent Anion Channel ◽

Atp Production ◽

Regular Arrangement ◽

Cell Energy

Elucidation of the mitochondrial regulatory mechanisms for the understanding of muscle bioenergetics and the role of mitochondria is a fundamental problem in cellular physiology and pathophysiology. The cytoskeleton (microtubules, intermediate filaments, microfilaments) plays a central role in the maintenance of mitochondrial shape, location, and motility. In addition, numerous interactions between cytoskeletal proteins and mitochondria can actively participate in the regulation of mitochondrial respiration and oxidative phosphorylation. In cardiac and skeletal muscles, mitochondrial positions are tightly fixed, providing their regular arrangement and numerous interactions with other cellular structures such as sarcoplasmic reticulum and cytoskeleton. This can involve association of cytoskeletal proteins with voltage-dependent anion channel (VDAC), thereby, governing the permeability of the outer mitochondrial membrane (OMM) to metabolites, and regulating cell energy metabolism. Cardiomyocytes and myocardial fibers demonstrate regular arrangement of tubulin beta-II isoform entirely co-localized with mitochondria, in contrast to other isoforms of tubulin. This observation suggests the participation of tubulin beta-II in the regulation of OMM permeability through interaction with VDAC. The OMM permeability is also regulated by the specific isoform of cytolinker protein plectin. This review summarizes and discusses previous studies on the role of cytoskeletal proteins in the regulation of energy metabolism and mitochondrial function, adenosine triphosphate (ATP) production, and energy transfer.

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Ultrastructural investigation of spontaneous pituitary gonadotroph cell adenomas in aging Sprague-Dawley rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100077086 ◽

1983 ◽

Vol 41 ◽

pp. 702-703

Author(s):

D. J. McComb ◽

J. Beri ◽

F. Zak ◽

K. Kovacs

Keyword(s):

Electron Microscopy ◽

Animal Model ◽

Epoxy Resin ◽

Immunoelectron Microscopy ◽

Tumor Type ◽

Gonadal Function ◽

Sprague Dawley ◽

Male And Female ◽

Reticulin Fibers ◽

Sprague Dawley Rats

Gonadotroph cell adenomas of the pituitary are infrequent in human patients and are not invariably associated with altered gonadal function. To date, no animal model of this tumor type exists. Herein, we describe spontaneous gonadotroph cell adenomas in old male and female Sprague-Dawley rats by histology, immunocytology and electron microscopy.The material consisted of the pituitaries of 27 male and 38 female Sprague Dawley rats, all 26 months of age or older, removed at routine autopsy. Sections of formal in-fixed, paraffin-embedded tissue were stained with hematoxylin-phloxine-saffron (HPS), the PAS method and the Gordon-Sweet technique for the demonstration of reticulin fibers. For immunostaining, sections were exposed to anti-rat β-LH, anti-ratβ-TSH, anti-rat PRL, anti-rat GH and anti-rat ACTH 1-39. For electron microscopy, tissue was fixed in 2.5% glutaraldehyde, postfixed in 1% OsO4 and embedded in epoxy-resin. Tissue fixed in 10% formalin, embedded in epoxy resin without osmification, was used for immunoelectron microscopy.

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Bioenergetic and metabolic impairments in Duchenne Muscular Dystrophy (DMD) patients' iPSC-derived cardiomyocytes

European Heart Journal ◽

10.1093/ehjci/ehaa946.3709 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

L Willi ◽

B Agranovich ◽

I Abramovich ◽

D Freimark ◽

M Arad ◽

...

Keyword(s):

Stress Test ◽

Young Male ◽

Induced Pluripotent Stem Cell ◽

Dystrophin Gene ◽

Energy System ◽

Basal Respiration ◽

Mitochondrial Activity ◽

Funding Source ◽

Atp Production ◽

Metabolic Impairments

Abstract Introduction DMD, an X-linked muscle degenerative fatal disease, is caused by mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. Treatments for DCM in DMD are limited to steroids and standard heart failure medications such as β-blockers and ACE-inhibitors, and therefore novel therapeutic modalities are urgently needed. Purpose We hypothesized that dystrophin mutations in DMD lead to cardiomyopathy-causing bioenergetic/metabolic impairments, which can be therapeutically targeted for improving cardiac function. Methods Induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) were generated from healthy volunteer and 3 DMD patients: young male (YM), adult male (AM) and adult female (AF). We investigated the bioenergetics, electrophysiology, mitochondrial and metabolic features of healthy and DMD iPSC-CMs using the Seahorse Flux analyzer, patch clamp, confocal fluorescence microscopy and Liquid chromatography mass spectrometry (LC-MS) technologies, respectively. Results To test the hypothesis, we measured respiration and glycolytic rates of healthy and DMD iPSC-CMs. Compared to healthy iPSC-CMs, in both AM and AF DMD, but not in YM DMD cardiomyocytes, there was a 75% decrease in ATP production, and 80% and 45% decrease in basal respiration, respectively. In agreement with the healthy-like bioenergetic status of YM, the iPSC-CMs showed no arrhythmias, in contrast to the prominent arrhythmias in AM and AF cardiomyocytes. To determine whether the impairment in the phosphorylation pathway (OXPHOS) affects glycolysis, we measured the cardiomyocytes' response to glycolytic stress test. These experiments showed that the glycolytic rates were similar in healthy and DMD iPSC-CMs. In agreement with impaired OXPHOS, mitochondrial activity measured by 3D life confocal microscopy was attenuated in the DMD male by 35%, compared to healthy cardiomyocytes. Furthermore, the metabolomic LC-MS analyses demonstrated significant differences in metabolite levels in YM, AM and AF DMD iPSC-CMs relative to healthy iPSC-CMs. For example, compared to healthy iPSC-CMs, there was a dramatic fall to undetected levels in phosphocreatine in both AM and AF, but not in YM DMD, indicating a dysfunctional phosphocreatine energy system. Conclusions DMD iPSC-CMs exhibit bioenergetic/metabolic impairments, which constitute novel targets for alleviating the cardiomyopathy in DMD patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): ISF - Israel Science Foundation

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Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

International Journal of Molecular Sciences ◽

10.3390/ijms22010424 ◽

2021 ◽

Vol 22 (1) ◽

pp. 424

Author(s):

Vlad F. Avram ◽

Imen Chamkha ◽

Eleonor Åsander-Frostner ◽

Johannes K. Ehinger ◽

Romulus Z. Timar ◽

...

Keyword(s):

Oxygen Consumption ◽

Mitochondrial Dysfunction ◽

Mitochondrial Respiration ◽

Complex I ◽

Ex Vivo ◽

Coupling Efficiency ◽

Human Platelets ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Cellular Models

Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.

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