scholarly journals Dramatic changes in mitochondrial substrate use at critically high temperatures: a comparative study using Drosophila

2021 ◽  
Vol 224 (6) ◽  
pp. jeb240960
Author(s):  
Lisa Bjerregaard Jørgensen ◽  
Johannes Overgaard ◽  
Florence Hunter-Manseau ◽  
Nicolas Pichaud
Keyword(s):  
High Temperatures ◽  
Heat Tolerance ◽  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Oxygen Consumption ◽  
Alternative Substrates ◽  
Atp Production ◽  
C Complex ◽  
Titration Protocol ◽  
Catalytic Capacity

ABSTRACTEctotherm thermal tolerance is critical to species distribution, but at present the physiological underpinnings of heat tolerance remain poorly understood. Mitochondrial function is perturbed at critically high temperatures in some ectotherms, including insects, suggesting that heat tolerance of these animals is linked to failure of oxidative phosphorylation (OXPHOS) and/or ATP production. To test this hypothesis, we measured mitochondrial oxygen consumption rate in six Drosophila species with different heat tolerance using high-resolution respirometry. Using a substrate–uncoupler–inhibitor titration protocol, we examined specific steps of the electron transport system to study how temperatures below, bracketing and above organismal heat limits affect mitochondrial function and substrate oxidation. At benign temperatures (19 and 30°C), complex I-supported respiration (CI-OXPHOS) was the most significant contributor to maximal OXPHOS. At higher temperatures (34, 38, 42 and 46°C), CI-OXPHOS decreased considerably, ultimately to very low levels at 42 and 46°C. The enzymatic catalytic capacity of complex I was intact across all temperatures and accordingly the decreased CI-OXPHOS is unlikely to be caused directly by hyperthermic denaturation/inactivation of complex I. Despite the reduction in CI-OXPHOS, maximal OXPHOS capacity was maintained in all species, through oxidation of alternative substrates – proline, succinate and, particularly, glycerol-3-phosphate – suggesting important mitochondrial flexibility at temperatures exceeding the organismal heat limit. Interestingly, this failure of CI-OXPHOS and compensatory oxidation of alternative substrates occurred at temperatures that correlated with species heat tolerance, such that heat-tolerant species could defend ‘normal’ mitochondrial function at higher temperatures than sensitive species. Future studies should investigate why CI-OXPHOS is perturbed and how this potentially affects ATP production rates.

scholarly journals Dramatic changes in mitochondrial substrate use at critically high temperatures: a comparative study using Drosophila

2020 ◽  
Author(s):  
Lisa Bjerregaard Jørgensen ◽  
Johannes Overgaard ◽  
Florence Hunter-Manseau ◽  
Nicolas Pichaud
Keyword(s):  
High Temperatures ◽  
Heat Tolerance ◽  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Oxygen Consumption ◽  
Alternative Substrates ◽  
Atp Production ◽  
Consumption Rates ◽  
C Complex ◽  
Titration Protocol

AbstractEctotherm thermal tolerance is critical to species distribution, but at present the physiological underpinnings of heat tolerance remain poorly understood. Mitochondrial function is perturbed at critically high temperatures in some ectotherms, including insects, suggesting that heat tolerance of these animals is linked to failure of oxidative phosphorylation (OXPHOS) and/or ATP production. To test this hypothesis we measured mitochondrial oxygen consumption rates in six Drosophila species with different heat tolerance using high-resolution respirometry. Using a substrate-uncoupler-inhibitor titration protocol we examined specific steps of the electron transport system to study how temperatures below, bracketing and above organismal heat limits affected mitochondrial function and substrate oxidation. At benign temperatures (19 and 30°C), complex I-supported respiration (CI-OXPHOS) was the most significant contributor to maximal OXPHOS. At higher temperatures (34, 38, 42 and 46°C), CI-OXPHOS decreased considerably, ultimately to very low levels at 42 and 46°C. The enzymatic catalytic capacity of complex I was intact across all temperatures and accordingly the decreased CI-OXPHOS is unlikely to be caused directly by hyperthermic denaturation/inactivation of complex I. Despite the reduction in CI-OXPHOS, maximal OXPHOS capacities were maintained in all species, through oxidation of alternative substrates; proline, succinate and, particularly, glycerol-3-phosphate, suggesting important mitochondrial flexibility at temperatures exceeding the organismal heat limit. Interestingly, this compensatory oxidation of alternative substrates occurred at temperatures that tended to correlate with species heat tolerance, such that heat-tolerant species could defend “normal” mitochondrial function at higher temperatures than sensitive species. Future studies should investigate why CI-OXPHOS is perturbed and how this potentially affects ATP production rates.

Effect of hyperthermia and acidosis on equine skeletal muscle mitochondrial oxygen consumption

2020 ◽  
pp. 1-10
Author(s):  
M.S. Davis ◽  
M.R. Fulton ◽  
A. Popken
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Oxidative Phosphorylation ◽  
Muscle Fatigue ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Complex I ◽  
Mitochondrial Oxygen Consumption ◽  
Biochemical Basis ◽  
Complex Ii

The skeletal muscle of exercising horses develops pronounced hyperthermia and acidosis during strenuous or prolonged exercise, with very high tissue temperature and low pH associated with muscle fatigue or damage. The purpose of this study was to evaluate the individual effects of physiologically relevant hyperthermia and acidosis on equine skeletal muscle mitochondrial function, using ex vivo measurement of oxygen consumption to assess the function of different mitochondrial elements. Fresh triceps muscle biopsies from 6 healthy unfit Thoroughbred geldings were permeabilised to permit diffusion of small molecular weight substrates through the sarcolemma and analysed in a high resolution respirometer at 38, 40, 42, and 44 °C, and pH=7.1, 6.5, and 6.1. Oxygen consumption was measured under conditions of non-phosphorylating (leak) respiration and phosphorylating respiration through Complex I and Complex II. Data were analysed using a one-way repeated measures ANOVA and data are expressed as mean ± standard deviation. Leak respiration was ~3-fold higher at 44 °C compared to 38 °C regardless of electron source (Complex I: 22.88±3.05 vs 8.08±1.92 pmol O2/mg/s), P=0.002; Complex II: 79.14±23.72 vs 21.43±11.08 pmol O2/mg/s, P=0.022), resulting in a decrease in efficiency of oxidative phosphorylation. Acidosis had minimal effect on mitochondrial respiration at pH=6.5, but pH=6.1 resulted in a 50% decrease in mitochondrial oxygen consumption. These results suggest that skeletal muscle hyperthermia decreases the efficiency of oxidative phosphorylation through increased leak respiration, thus providing a specific biochemical basis for hyperthermia-induced muscle fatigue. The effect of myocellular acidosis on mitochondrial respiration was minimal under typical levels of acidosis, but atypically severe acidosis can lead to impairment of mitochondrial function.

Abstract 15731: Sildenafil Improves Mitochondrial Function in Failing Single Ventricles

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anastacia M Garcia ◽  
Carissa A Miyano ◽  
Raleigh Joschner ◽  
Matthew Stone ◽  
Brian L Stauffer ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Mitochondrial Function ◽  
Complex I ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Mitochondrial Oxygen Consumption ◽  
Ventricular Tissue ◽  
Substrate Inhibitor ◽  
Phosphodiesterase 5 ◽  
One Way Anova

Introduction: Heart failure (HF) remains a leading cause of death and indication for transplant in single ventricle congenital heart disease (SV). However, little is known regarding the molecular mechanisms leading to HF in SV. The purpose of this study was to characterize mitochondrial function in the myocardium of failing (SVHF) and non-failing (SVNF) SV patients compared to biventricular NF controls (BVNF). Furthermore, we investigated the effect of ex vivo treatment with the phosphodiesterase-5 inhibitor (PDE5i) sildenafil on mitochondrial function. Methods: Freshly explanted ventricular tissue was saponin permeabilized and mitochondrial oxygen consumption was measured sequentially throughout the electron transport system using SUbstrate-Inhibitor-Titration (“SUIT”) protocols and an Oroboros O2k high resolution respirometer. Permeabilized ventricular tissue was treated for 40 min with sildenafil [1μM] prior to measurement of oxygen consumption. A Western blot for PDE5 was performed in isolated mitochondrial proteins from SVHF subjects ± PDE5i. Results: Compared to BVNF (n=15) and SVNF (n=6), SVHF (n=8) hearts have decreased function of Complex I and Complex I and II (A, B), and decreased maximal respiration (C), all of which improve with acute ex vivo treatment with sildenafil in SVHF (SVHF+PDE5i, n=6). Importantly, mitochondrial function is impaired in BVNF+PDE5i (n=5) and SVNF+PDE5i hearts (n=5) (A-C, one-way Anova p<0.05). PDE5 protein is expressed in SVHF mitochondria, but expression is not affected by ex vivo PDE5i treatment (D). Conclusions: Our results indicate that mitochondrial function is impaired in SVHF, PDE5 protein is expressed in SVHF mitochondria, and PDE5i improves mitochondrial function in SVHF, but may be detrimental to mitochondrial function in SVNF and BVNF. Together these data suggest that mitochondrial PDE5 is a potential therapeutic target, but that indiscriminate use of PDE5i in SV patients may not be advisable.

scholarly journals The Effect of Branched Chain Amino Acids on Skeletal Muscle Mitochondrial Function in Young and Elderly Adults

2010 ◽  
Vol 95 (2) ◽  
pp. 894-902 ◽  
Author(s):  
Laura L. Tatpati ◽  
Brian A. Irving ◽  
Andrea Tom ◽  
Maureen L. Bigelow ◽  
Katherine Klaus ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Mitochondrial Function ◽  
Complex I ◽  
The Elderly ◽  
Branched Chain Amino Acids ◽  
Saline Infusion ◽  
Elderly Adults ◽  
Atp Production ◽  
Branched Chain

Abstract Context: A reduction in maximal mitochondrial ATP production rate (MAPR) and mitochondrial DNA (mtDNA) abundance occurs with age in association with muscle weakness and reduced endurance in elderly people. Branched chain amino acids (BCAA) have been extensively used to improve physical performance. Objective: The objective was to determine whether an 8-h infusion of BCAA enhances MAPR equally in healthy young and elderly adults. Methods: Using a crossover study design, we compared the effect BCAA vs. saline infusion in 12 young (23.0 ± 0.8 yr) and 12 elderly (70.7 ± 1.1 yr) participants matched for sex and body mass index. Skeletal muscle MAPR and mtDNA abundance were measured in muscle biopsy samples obtained before and at the end of the 8-h infusion. Results: In young participants, MAPR with the substrates glutamate plus malate (supplying electrons to complex I) and succinate plus rotenone (complex II) increased in response to BCAA infusion, relative to a decline in MAPR in response to the saline infusion. In contrast, MAPR was unaffected by BCAA infusion in the elderly participants. Moreover, mtDNA abundance was lower in the elderly compared with the young participants but was unaffected by the BCAA infusion. Insulin and C-peptide concentrations declined over time during the saline infusion, but these declines were prevented by the BCAA infusion. Conclusions: BCAA increased skeletal muscle MAPR in the young participants in comparison with saline, but this effect was not seen in the elderly participants indicating, that unlike in the young, BCAA does not increase muscle mitochondrial function in the elderly.

A new insight into the molecular hydrogen effect on coenzyme Q and mitochondrial function of rats

2020 ◽  
Vol 98 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Anna Gvozdjáková ◽  
Jarmila Kucharská ◽  
Branislav Kura ◽  
Ol’ga Vančová ◽  
Zuzana Rausová ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Phosphorylation ◽  
Respiratory Chain ◽  
Mitochondrial Function ◽  
Complex I ◽  
Molecular Hydrogen ◽  
Coenzyme Q ◽  
Complex Ii ◽  
Atp Production ◽  
Q Cycle

Mitochondria are the major source of cellular energy metabolism. In the cardiac cells, mitochondria produce by way of the oxidative phosphorylation more than 90% of the energy supply in the form of ATP, which is utilized in many ATP-dependent processes, like cycling of the contractile proteins or maintaining ion gradients. Reactive oxygen species (ROS) are by-products of cellular metabolism and their levels are controlled by intracellular antioxidant systems. Imbalance between ROS and the antioxidant defense leads to oxidative stress and oxidative changes to cellular biomolecules. Molecular hydrogen (H2) has been proved as beneficial in the prevention and therapy of various diseases including cardiovascular disorders. It selectively scavenges hydroxyl radical and peroxynitrite, reduces oxidative stress, and has anti-inflammatory and anti-apoptotic effects. The effect of H2 on the myocardial mitochondrial function and coenzyme Q levels is not well known. In this paper, we demonstrated that consumption of H2-rich water (HRW) resulted in stimulated rat cardiac mitochondrial electron respiratory chain function and increased levels of ATP production by Complex I and Complex II substrates. Similarly, coenzyme Q9 levels in the rat plasma, myocardial tissue, and mitochondria were increased and malondialdehyde level in plasma was reduced after HRW administration. Based on obtained data, we hypothesize a new metabolic pathway of the H2 effect in mitochondria on the Q-cycle and in mitochondrial respiratory chain function. The Q-cycle contains three coenzyme Q forms: coenzyme Q in oxidized form (ubiquinone), radical form (semiquinone), or reduced form (ubiquinol). H2 may be a donor of both electron and proton in the Q-cycle and thus we can suppose stimulation of coenzyme Q production. When ubiquinone is reduced to ubiquinol, lipid peroxidation is reduced. Increased CoQ9 concentration can stimulate electron transport from Complex I and Complex II to Complex III and increase ATP production via mitochondrial oxidative phosphorylation. Our results indicate that H2 may function to prevent/treat disease states with disrupted myocardial mitochondrial function.

scholarly journals Adaptation of mitochondrial expression and ATP production in dedifferentiating vascular smooth muscle cells

2017 ◽  
Vol 95 (12) ◽  
pp. 1473-1479 ◽  
Author(s):  
Celena Scheede-Bergdahl ◽  
Andreas Bergdahl
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Mitochondrial Function ◽  
Complex I ◽  
Clinical Manifestations ◽  
Western World ◽  
Aortic Tissue ◽  
Atp Production

Atherosclerosis is one of the leading causes of morbidity and mortality in the Western world. Although the clinical manifestations of this disease are well documented, the etiology and progression remain to be fully understood. Recently, the mitochondria have been implicated in important cellular processes involved in development of atherosclerosis. Despite the link between mitochondria and atherosclerosis, early-phase mechanisms of the disease have yet to be elucidated. The aim of this project was to explore the role of mitochondria in vascular smooth muscle (VSMC) dedifferentiation. A murine in vitro model, involving organ culture of aortic tissue in serum-free media, was used. Mitochondrial function was measured by high-resolution respirometry. Proteins associated with the VSMC phenotype switch, as well as mitochondrial density, were assessed by immunoblotting. The findings show that intrinsic mitochondrial Complex I activity is significantly upregulated during VSMC dedifferentiation. Diminished coupling between phosphorylation and oxidation was also found, indicating a greater ADP:ATP ratio. This data suggests increased leak in the electron transport chain and altered mitochondrial function specifically at Complex I. This project provides important information regarding the role of mitochondria in the early atherosclerotic process and that detectable changes in mitochondrial function and expression are related to VSMC dedifferentiation.

Protein kinase C-ϵ modulates mitochondrial function and active Na+ transport after oxidant injury in renal cells

2004 ◽  
Vol 286 (2) ◽  
pp. F307-F316 ◽  
Author(s):  
Grażyna Nowak ◽  
Diana Bakajsova ◽  
Ginger L. Clifton
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Atpase Activity ◽  
Mitochondrial Function ◽  
Complex I ◽  
Primary Cultures ◽  
Oxidant Injury ◽  
Atp Production ◽  
Kinase C ◽  
Renal Proximal Tubular Cells

The aim of this study was to determine whether protein kinase C-ϵ (PKC-ϵ) is involved in the repair of mitochondrial function and/or active Na+ transport after oxidant injury in renal proximal tubular cells (RPTC). Sublethal injury was produced in primary cultures of RPTC using tert-butylhydroperoxide (TBHP), and the recovery of functions was examined. PKC-ϵ was activated three- to fivefold after injury. Active PKC-ϵ translocated to the mitochondria. Basal oxygen consumption (Qo2), uncoupled Qo2, and ATP production decreased 58, 60, and 41%, respectively, at 4 h and recovered by day 4 after injury. At 4 h, complex I-coupled respiration decreased 50% but complex II- and IV-coupled respirations were unchanged. Inhibition of PKC-ϵ translocation using a peptide selective inhibitor, PKC-ϵV1-2, reduced decreases in basal and uncoupled Qo2 values and increased complex I-linked respiration in TBHP-injured RPTC at 4 h of recovery. Furthermore, PKC-ϵV1-2 prevented decreases in ATP production in injured RPTC. Na+-K+-ATPase activity and ouabain-sensitive 86Rb+ uptake were decreased by 60 and 53%, respectively, at 4 h of recovery. Inhibition of PKC-ϵ activation prevented a decline in Na+-K+-ATPase activity and reduced decreases in ouabain-sensitive 86Rb+ uptake. We conclude that during early repair after oxidant injury in RPTC 1) PKC-ϵ is activated and translocated to mitochondria; 2) PKC-ϵ activation decreases mitochondrial respiration, electron transport rate, and ATP production by reducing complex I-linked respiration; and 3) PKC-ϵ mediates decreases in active Na+ transport and Na+-K+-ATPase activity. These data show that PKC-ϵ activation after oxidant injury in RPTC is involved in the decreases in mitochondrial function and active Na+ transport and that inhibition of PKC-ϵ activation promotes the repair of these functions.

scholarly journals Prenatal acoustic programming of mitochondrial function for high temperatures in an arid-adapted bird

2021 ◽  
Vol 288 (1964) ◽  
Author(s):  
Eve Udino ◽  
Julia M. George ◽  
Matthew McKenzie ◽  
Anaïs Pessato ◽  
Ondi L. Crino ◽  
...  
Keyword(s):  
High Temperatures ◽  
Prenatal Exposure ◽  
Mitochondrial Function ◽  
Production Efficiency ◽  
Developmental Programming ◽  
Atp Production ◽  
Thermal Environments ◽  
Mitochondrial Efficiency ◽  
Underlying Mechanisms ◽  
Acoustic Sensitivity

Sound is an essential source of information in many taxa and can notably be used by embryos to programme their phenotypes for postnatal environments. While underlying mechanisms are mostly unknown, there is growing evidence for the involvement of mitochondria—main source of cellular energy (i.e. ATP)—in developmental programming processes. Here, we tested whether prenatal sound programmes mitochondrial metabolism. In the arid-adapted zebra finch, prenatal exposure to ‘heat-calls’—produced by parents incubating at high temperatures—adaptively alters nestling growth in the heat. We measured red blood cell mitochondrial function, in nestlings exposed prenatally to heat- or control-calls, and reared in contrasting thermal environments. Exposure to high temperatures always reduced mitochondrial ATP production efficiency. However, as expected to reduce heat production, prenatal exposure to heat-calls improved mitochondrial efficiency under mild heat conditions. In addition, when exposed to an acute heat-challenge, LEAK respiration was higher in heat-call nestlings, and mitochondrial efficiency low across temperatures. Consistent with its role in reducing oxidative damage, LEAK under extreme heat was also higher in fast growing nestlings. Our study therefore provides the first demonstration of mitochondrial acoustic sensitivity, and brings us closer to understanding the underpinning of acoustic developmental programming and avian strategies for heat adaptation.

scholarly journals PSV-25 Mitochondrial function of skeletal muscle early postmortem is influenced by cattle breed and temperature

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 334-334
Author(s):  
Patricia Ramos ◽  
Chengcheng Li ◽  
Mauricio Elzo ◽  
Stephanie Wohlgemuth ◽  
Tracy Scheffler
Keyword(s):  
Skeletal Muscle ◽  
Meat Quality ◽  
Heat Tolerance ◽  
Mitochondrial Function ◽  
Complex I ◽  
Citrate Synthase ◽  
Bos Taurus ◽  
Cattle Breed ◽  
Longissimus Lumborum ◽  
Early Postmortem

Abstract Functional properties and integrity of skeletal muscle mitochondria during the early postmortem period may influence development of meat quality traits, such as tenderness. Angus typically produce more tender beef than Brahman, a Bos taurus indicus subspecies known for heat tolerance. Thus, our objectives were to assess mitochondrial function in muscle collected early postmortem from Angus and Brahman cattle; and to evaluate the effect of normal and elevated temperature on mitochondria function. Longissimus lumborum was collected at 1h postmortem from Angus and Brahman steers, and high resolution respirometry was used to assess mitochondrial function in permeabilized muscle fibers at two temperatures (38.5 and 40.0°C). The main effects of breed, temperature, and their interaction were tested. On a tissue weight basis, parameters of respiratory function were not influenced by breed or temperature, though Brahman exhibited numerically greater values for respiration supported by complex I, complex I+II, and complex II substrates. Citrate synthase activity, a marker of mitochondria content, was affected by breed (P = 0.049). Consequently, oxygen consumption rate (OCR) data were normalized to citrate synthase activity. After normalization for mitochondrial content, the overall mitochondria OCR pattern changed, revealing differences among breeds for proton leak respiration (P = 0.045), as well as a persistent interaction effect primarily related to reduced OCR in mitochondria from Brahman at 40.0°C. In addition, the ratio of OCR for leak relative to complex I+II phosphorylation was lower in Brahman, evidencing greater coupling. However, mean coupling ratios for both Angus and Brahman support that respiration and phosphorylation were well-coupled for both breeds even at 1h postmortem. Thus, mitochondria retain functional capacity and integrity at 1h postmortem; and mitochondria properties may be related to differences in heat tolerance and meat quality development between cattle subspecies.

scholarly journals Activation of ERK1/2 pathway mediates oxidant-induced decreases in mitochondrial function in renal cells

2006 ◽  
Vol 291 (4) ◽  
pp. F840-F855 ◽  
Author(s):  
Grażyna Nowak ◽  
Ginger L. Clifton ◽  
Malinda L. Godwin ◽  
Diana Bakajsova
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Complex I ◽  
Protective Effects ◽  
Atp Production ◽  
Aconitase Activity ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Pathway Inhibition ◽  
Complex I Activity

Previously, we showed that oxidant exposure in renal proximal tubular cells (RPTC) induces mitochondrial dysfunction mediated by PKC-ε. This study examined the role of ERK1/2 in mitochondrial dysfunction induced by oxidant injury and whether PKC-ε mediates its effects on mitochondrial function through the Raf-MEK1/2-ERK1/2 pathway. Sublethal injury produced by tert-butylhydroperoxide (TBHP) resulted in three- to fivefold increase in phosphorylation of ERK1/2 and p38 but not JNK. This was followed by decreases in basal and uncoupled respirations (41%), state 3 respiration and ATP production coupled to complex I (46%), and complex I activity (42%). Oxidant exposure decreased aconitase activity 30% but not pyruvate, α-ketoglutarate, and malate dehydrogenase activities. Inhibition of ERK1/2 restored basal and state 3 respirations, ΔΨm, ATP production, and complex I activity but not aconitase activity. In contrast, activation of ERK1/2 by expression of constitutively active MEK1 suppressed basal, uncoupled, and state 3 respirations in noninjured RPTC to the levels observed in TBHP-injured RPTC. MEK1/2 inhibition did not change Akt or p38 phosphorylation, demonstrating that the protective effect of MEK1/2 inhibitor was not due to activation of Akt or inhibition of p38 pathway. Inhibition of PKC-ε did not block TBHP-induced ERK1/2 phosphorylation in whole RPTC or in mitochondria. We conclude that 1) oxidant-induced activation of ERK1/2 but not p38 or JNK reduces mitochondrial respiration and ATP production by decreasing complex I activity and substrate oxidation through complex I, 2) citric acid cycle dehydrogenases are not under control of the ERK1/2 pathway in oxidant-injured RPTC, 3) the protective effects of ERK1/2 inhibition are not due to activation of Akt, and 4) ERK1/2 and PKC-ε mediate oxidant-induced mitochondrial dysfunction through independent pathways.

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