High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates

2007 ◽  
Vol 409 (2) ◽  
pp. 491-499 ◽  
Author(s):  
Florian L. Muller ◽  
Yuhong Liu ◽  
Muhammad A. Abdul-Ghani ◽  
Michael S. Lustgarten ◽  
Arunabh Bhattacharya ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Complex I ◽  
Superoxide Production ◽  
Complex Ii ◽  
Reverse Electron Transfer ◽  
Physiological Importance ◽  
Palmitoyl Carnitine ◽  
Skeletal Muscle Mitochondria ◽  
Carbonyl Cyanide ◽  
High Concentrations

Despite the considerable interest in superoxide as a potential cause of pathology, the mechanisms of its deleterious production by mitochondria remain poorly understood. Previous studies in purified mitochondria have found that the highest rates of superoxide production are observed with succinate-driven reverse-electron transfer through complex I, although the physiological importance of this pathway is disputed because it necessitates high concentrations of succinate and is thought not to occur when NAD is in the reduced state. However, very few studies have examined the rates of superoxide production with mitochondria respiring on both NADH-linked (e.g. glutamate) and complex II-linked substrates. In the present study, we find that the rates of superoxide production (measured indirectly as H2O2) with glutamate+succinate (∼1100 pmol of H2O2·min−1·mg−1) were unexpectedly much higher than with succinate (∼400 pmol of H2O2·min−1·mg−1) or glutamate (∼80 pmol of H2O2·min−1·mg−1) alone. Superoxide production with glutamate+succinate remained high even at low substrate concentrations (<1 mM), was decreased by rotenone and was completely eliminated by FCCP (carbonyl cyanide p-trifluoromethoxyphenylhydrazone), indicating that it must in large part originate from reverse-electron transfer through complex I. Similar results were obtained when glutamate was replaced with pyruvate, α-ketoglutarate or palmitoyl carnitine. In contrast, superoxide production was consistently lowered by the addition of malate (malate+succinate ∼30 pmol of H2O2·min−1·mg−1). We propose that the inhibitory action of malate on superoxide production can be explained by oxaloacetate inhibition of complex II. In summary, the present results indicate that reverse-electron transfer-mediated superoxide production can occur under physiologically realistic substrate conditions and suggest that oxaloacetate inhibition of complex II may be an adaptive mechanism to minimize this.

scholarly journals Skeletal muscle mitochondrial function and exercise capacity are not impaired in mice with knockout of STAT3

2019 ◽  
Vol 127 (4) ◽  
pp. 1117-1127
Author(s):  
Jessica R. Dent ◽  
Byron Hetrick ◽  
Shahriar Tahvilian ◽  
Abha Sathe ◽  
Keenan Greyslak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Electron Transport ◽  
Complex I ◽  
Physiological Function ◽  
Oxidative Capacity ◽  
Signal Transducer ◽  
Muscle Mitochondria ◽  
Complex Ii ◽  
Skeletal Muscle Mitochondria ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) was recently found to be localized to mitochondria in a number of tissues and cell types, where it modulates oxidative phosphorylation via interactions with the electron transport proteins, complex I and complex II. Skeletal muscle is densely populated with mitochondria although whether STAT3 contributes to skeletal muscle oxidative capacity is unknown. In the present study, we sought to elucidate the contribution of STAT3 to mitochondrial and skeletal muscle function by studying mice with muscle-specific knockout of STAT3 (mKO). First, we developed a novel flow cytometry-based approach to confirm that STAT3 is present in skeletal muscle mitochondria. However, contrary to findings in other tissue types, complex I and complex II activity and maximal mitochondrial respiratory capacity in skeletal muscle were comparable between mKO mice and floxed/wild-type littermates. Moreover, there were no genotype differences in endurance exercise performance, skeletal muscle force-generating capacity, or the adaptive response of skeletal muscle to voluntary wheel running. Collectively, although we confirm the presence of STAT3 in skeletal muscle mitochondria, our data establish that STAT3 is dispensable for mitochondrial and physiological function in skeletal muscle. NEW & NOTEWORTHY Whether signal transducer and activator of transcription 3 (STAT3) can regulate the activity of complex I and II of the electron transport chain and mitochondrial oxidative capacity in skeletal muscle, as it can in other tissues, is unknown. By using a mouse model lacking STAT3 in muscle, we demonstrate that skeletal muscle mitochondrial and physiological function, both in vivo and ex vivo, is not impacted by the loss of STAT3.

scholarly journals Effects of vitamin A deficiency on mitochondrial function in rat liver and heart

2000 ◽  
Vol 84 (6) ◽  
pp. 927-934 ◽  
Author(s):  
Ernesto Estornell ◽  
José R. Tormo ◽  
Pilar Marín ◽  
Jaime Renau-Piqueras ◽  
Joaquín Timoneda ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Vitamin A ◽  
Complex I ◽  
Vitamin A Deficiency ◽  
Coenzyme Q ◽  
Control Diet ◽  
Male Rats ◽  
Heart Mitochondria ◽  
Complex Ii ◽  
Oxidation Rates

The aim of this study was to investigate comparative effects of vitamin A deficiency on respiratory activity and structural integrity in liver and heart mitochondria. Male rats were fed a liquid control diet (control rats) or a liquid vitamin A-deficient diet (vitamin A-deficient rats) for 50 days. One group of vitamin-A deficient rats was refed a control diet for 15 days (vitamin A-recovered rats). To assess the respiratory function of mitochondria the contents of coenzyme Q (ubiquinone, CoQ), cytochrome c and the activities of the whole electron transport chain and of each of its respiratory complexes were evaluated. Chronic vitamin A deficiency promoted a significant increase in the endogenous coenzyme Q content in liver and heart mitochondria when compared with control values. Vitamin A deficiency induced a decrease in the activity of complex I (NADH–CoQ reductase) and complex II (succinate–CoQ reductase) and in the levels of complex I and cytochrome c in heart mitochondria. However, NADH and succinate oxidation rates were maintained at the control levels due to an increase in the CoQ content in accordance with the kinetic behaviour of CoQ as an homogeneous pool. On the contrary, the high CoQ content did not affect the electron-transfer rate in liver mitochondria, whose integrity was preserved from the deleterious effects of the vitamin A deficiency. Ultrastuctural assessment of liver and heart showed that vitamin A deficiency did not induce appreciable alterations in the morphology of their mitochondria. After refeeding the control diet, serum retinol, liver and heart CoQ content and the activity of complex I and complex II in heart mitochondria returned to normality. However, the activities of both whole electron transfer chain and complex I in liver were increased over the control values. The interrelationships between physiological antioxidants in biological membranes and the beneficial effects of their administration in mitochondrial diseases are discussed.

scholarly journals Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury

2017 ◽  
Vol 37 (12) ◽  
pp. 3649-3658 ◽  
Author(s):  
Anna Stepanova ◽  
Anja Kahl ◽  
Csaba Konrad ◽  
Vadim Ten ◽  
Anatoly S Starkov ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Brain Ischemia ◽  
Complex I ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Brain Mitochondria ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Reverse Electron Transfer ◽  
Novel Target

Ischemic stroke is one of the most prevalent sources of disability in the world. The major brain tissue damage takes place upon the reperfusion of ischemic tissue. Energy failure due to alterations in mitochondrial metabolism and elevated production of reactive oxygen species (ROS) is one of the main causes of brain ischemia-reperfusion (IR) damage. Ischemia resulted in the accumulation of succinate in tissues, which favors the process of reverse electron transfer (RET) when a fraction of electrons derived from succinate is directed to mitochondrial complex I for the reduction of matrix NAD+. We demonstrate that in intact brain mitochondria oxidizing succinate, complex I became damaged and was not able to contribute to the physiological respiration. This process is associated with a decline in ROS release and a dissociation of the enzyme's flavin. This previously undescribed phenomenon represents the major molecular mechanism of injury in stroke and induction of oxidative stress after reperfusion. We also demonstrate that the origin of ROS during RET is flavin of mitochondrial complex I. Our study highlights a novel target for neuroprotection against IR brain injury and provides a sensitive biochemical marker for this process.

scholarly journals A Link between Mitochondrial Dysregulation and Idiopathic Autism Spectrum Disorder (ASD): Alterations in Mitochondrial Respiratory Capacity and Membrane Potential

2021 ◽  
Vol 43 (3) ◽  
pp. 2238-2252
Author(s):  
Hazirah Hassan ◽  
Fazaine Zakaria ◽  
Suzana Makpol ◽  
Norwahidah Abdul Karim
Keyword(s):  
Autism Spectrum Disorder ◽  
Electron Transfer ◽  
Membrane Potential ◽  
Mitochondrial Function ◽  
Complex I ◽  
Autism Spectrum ◽  
Complex Iv ◽  
Respiratory Capacity ◽  
Complex Ii ◽  
Mitochondrial Respiratory

Autism spectrum disorder (ASD) is a neurological disorder triggered by various factors through complex mechanisms. Research has been done to elucidate the potential etiologic mechanisms in ASD, but no single cause has been confirmed. The involvement of oxidative stress is correlated with ASD and possibly affects mitochondrial function. This study aimed to elucidate the link between mitochondrial dysregulation and idiopathic ASD by focusing on mitochondrial respiratory capacity and membrane potential. Our findings showed that mitochondrial function in the energy metabolism pathway was significantly dysregulated in a lymphoblastoid cell line (LCL) derived from an autistic child (ALCL). Respiratory capacities of oxidative phosphorylation (OXPHOS), electron transfer of the Complex I and Complex II linked pathways, membrane potential, and Complex IV activity of the ALCL were analyzed and compared with control cell lines derived from a developmentally normal non-autistic sibling (NALCL). All experiments were performed using high-resolution respirometry. Respiratory capacities of OXPHOS, electron transfer of the Complex I- and Complex II-linked pathways, and Complex IV activity of the ALCL were significantly higher compared to healthy controls. Mitochondrial membrane potential was also significantly higher, measured in the Complex II-linked pathway during LEAK respiration and OXPHOS. These results indicate the abnormalities in mitochondrial respiratory control linking mitochondrial function with autism. Correlating mitochondrial dysfunction and autism is important for a better understanding of ASD pathogenesis in order to produce effective interventions.

Studies in polymerization XVII. The initiation of vinyl polymerization by tetrakis (triphenyl phosphite) nickel (0)

1967 ◽  
Vol 297 (1451) ◽  
pp. 425-439 ◽  
Keyword(s):  
Free Radical ◽  
High Frequency ◽  
Complex I ◽  
Methylene Chloride ◽  
Metal Carbonyl ◽  
Frequency Factor ◽  
Triphenyl Phosphite ◽  
Complex Ii ◽  
High Concentrations ◽  
Active Initiator

It has been found that tetrakis (triphenyl phosphite) nickel (0), in the presence of a suitable organic halide, is a very active initiator of free-radical polymerization. This paper describes a detailed kinetic study of the initiation of the polymerization of methyl methacrylate at 25 °C by the system Ni{P(O Ph ) 3 } 4 + CCl 4 , together with some observations on the systems in which ethyl trichloracetate and methylene chloride are the halide components. The reaction has been studied in benzene, ethyl acetate, dioxan and NN -dimethylformamide solutions, as well as in bulk monomer. In general, the mechanism of initiation resembles that previously reported for metal carbonyls. The primary step, which becomes rate-determining at sufficiently high halide concentrations, is an S N 2 process in which a triphenyl phosphite ligand is replaced by monomer or a solvent with electron-donating properties, with formation of a complex (I). Reaction of this with the halide produces a second complex (II) which yields a free radical on decomposition. Addition of triphenyl phosphite reverses the primary step and thus reduces the concentration of complex (I) and the rate of radical formation. Carbon monoxide is a powerful inhibitor, and appears to function by deactivation of complex (II). This initiating system differs from most metal carbonyl systems in that it is entirely free from inhibition at high concentrations of initiator. Measurements of the yield of polymer show that two free radicals are formed by each molecule of the nickel derivative which decomposes, presumably corresponding to the oxidation Ni 0 → Ni II . Although Ni{P(O Ph ) 3 } 4 is stable in the solid state, its half-life in bulk monomer at 25 °C is only 1 h. The primary step has an activation energy of 25∙2 kcal/mole and a high frequency factor, which may be the result of steric overcrowding in the molecule of the nickel derivative.

scholarly journals Design and use of peptide-based antibodies decreasing superoxide production by mitochondrial complex I and complex II

Biopolymers ◽  
2011 ◽  
Vol 96 (2) ◽  
pp. 207-221 ◽  
Author(s):  
Patrick T. Kang ◽  
June Yun ◽  
Pravin P. T. Kaumaya ◽  
Yeong-Renn Chen
Keyword(s):  
Complex I ◽  
Superoxide Production ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Complex Ii
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