scholarly journals Complex effects of pH on ROS from mitochondrial complex II driven complex I reverse electron transport challenge its role in tissue reperfusion injury

2020 ◽  
Author(s):  
Alexander S. Milliken ◽  
Chaitanya A. Kulkarni ◽  
Paul S. Brookes
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Ischemia Reperfusion ◽  
Mitochondrial Complex ◽  
Complex Ii ◽  
Effects Of Ph ◽  
Cellular Necrosis ◽  
Reverse Electron Transport ◽  
The Impact

ABSTRACTGeneration of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane ΔpH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mitochondria under conditions which mimic the onset of reperfusion (i.e., high [ADP]). We show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by ΔpH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed.

scholarly journals Physiologic Implications of Reactive Oxygen Species Production by Mitochondrial Complex I Reverse Electron Transport

Antioxidants ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 285 ◽  
Author(s):  
John O. Onukwufor ◽  
Brandon J. Berry ◽  
Andrew P. Wojtovich
Keyword(s):  
Reactive Oxygen Species ◽  
Electron Transport ◽  
Complex I ◽  
Reactive Oxygen ◽  
Reverse Direction ◽  
Mitochondrial Complex I ◽  
Ros Production ◽  
Oxygen Species ◽  
Mitochondrial Complex ◽  
Reverse Electron Transport

Mitochondrial reactive oxygen species (ROS) can be either detrimental or beneficial depending on the amount, duration, and location of their production. Mitochondrial complex I is a component of the electron transport chain and transfers electrons from NADH to ubiquinone. Complex I is also a source of ROS production. Under certain thermodynamic conditions, electron transfer can reverse direction and reduce oxygen at complex I to generate ROS. Conditions that favor this reverse electron transport (RET) include highly reduced ubiquinone pools, high mitochondrial membrane potential, and accumulated metabolic substrates. Historically, complex I RET was associated with pathological conditions, causing oxidative stress. However, recent evidence suggests that ROS generation by complex I RET contributes to signaling events in cells and organisms. Collectively, these studies demonstrate that the impact of complex I RET, either beneficial or detrimental, can be determined by the timing and quantity of ROS production. In this article we review the role of site-specific ROS production at complex I in the contexts of pathology and physiologic signaling.

scholarly journals SQR mediates therapeutic effects of H2S by targeting mitochondrial electron transport to induce mitochondrial uncoupling

2020 ◽  
Vol 6 (35) ◽  
pp. eaaz5752
Author(s):  
Jia Jia ◽  
Zichuang Wang ◽  
Minjie Zhang ◽  
Caiyun Huang ◽  
Yanmei Song ◽  
...  
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Adenosine Monophosphate ◽  
Therapeutic Effects ◽  
Mitochondrial Complex ◽  
Mitochondrial Uncoupling ◽  
Quinone Oxidoreductase ◽  
Complex Iv ◽  
Reverse Electron Transport ◽  
Mediated Oxidation

Hydrogen sulfide (H2S) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes H2S. Therefore, SQR is assumed to inhibit H2S signaling. We now report that SQR-mediated oxidation of H2S drives reverse electron transport (RET) at mitochondrial complex I, which, in turn, repurposes mitochondrial function to superoxide production. Unexpectedly, complex I RET, a process dependent on high mitochondrial membrane potential, induces superoxide-dependent mitochondrial uncoupling and downstream activation of adenosine monophosphate–activated protein kinase (AMPK). SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by H2S. Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of H2S following intracerebral hemorrhage. To conclude, SQR mediates H2S signaling and therapeutic effects by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Moreover, SQR is a previously unrecognized target for developing non-protonophore uncouplers with broad clinical implications.

scholarly journals Structural basis for a complex I mutation that blocks pathological ROS production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhan Yin ◽  
Nils Burger ◽  
Duvaraka Kula-Alwar ◽  
Dunja Aksentijević ◽  
Hannah R. Bridges ◽  
...  
Keyword(s):  
Point Mutation ◽  
Complex I ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Ros Production

AbstractMitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

scholarly journals Alternative Mitochondrial Electron Transfer as a Novel Strategy for Neuroprotection

2011 ◽  
Vol 286 (18) ◽  
pp. 16504-16515 ◽  
Author(s):  
Yi Wen ◽  
Wenjun Li ◽  
Ethan C. Poteet ◽  
Luokun Xie ◽  
Cong Tan ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Free Radical ◽  
Cerebral Ischemia ◽  
Complex I ◽  
Focal Cerebral Ischemia ◽  
Neurological Diseases ◽  
Ischemia Reperfusion ◽  
Free Radical Scavengers ◽  
Mitochondrial Complex ◽  
Novel Strategy

Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled by N-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.

Abstract 404: High-throughput Screening Reveals the Mitochondrial Complex I Inhibitor Nornicotine is Cardioprotective in Ischemia-reperfusion Injury When Delivered at Reperfusion

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Jimmy Zhang ◽  
Marcin K Karcz ◽  
Sergiy M Nadtochiy ◽  
Paul S Brookes
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Functional Recovery ◽  
Complex I ◽  
Ischemia Reperfusion ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Early Reperfusion ◽  
Perfused Hearts

Background: To date, there are no FDA-approved therapies for the reduction of infarct size in acute myocardial infarction. Previously, we developed a cell-based phenotypic assay of ischemia-reperfusion (IR) injury, which was used to identify novel cytoprotective agents delivered prior to ischemia. Herein, we sought to identify cytoprotective agents in a more clinically relevant model: drug delivery at reperfusion, and to investigate possible underlying mechanisms of protection. Methods: Primary adult mouse cardiomyocytes were subjected to simulated IR injury using a modified Seahorse XF24 apparatus with drug addition at the onset of reperfusion. Cell death was estimated using LDH release. Drugs which protected cardiomyocytes in vitro were tested in a Langendorff model of IR injury, measuring functional recovery and infarct size. In separate experiments, metabolites extracted from perfused hearts were resolved by HPLC. Results: Nornicotine was identified as a cardioprotective agent in the screen. In perfused hearts, 10 nM nornicotine injected at the onset of reperfusion improved functional recovery and decreased in infarct size (13.1% ± 2.4 vs 49.2% ± 2.5 in non-treated hearts, p<0.05, n=16-20). Nornicotine also exhibited profound inhibitory effects on mitochondrial complex I activity. Succinate is known to accumulate in ischemia, and its rapid consumption during early reperfusion exacerbates reperfusion injury via ROS generation from electron backflow through complex I [PMID: 25383517]. In non-treated hearts, we confirmed that high post ischemic levels of succinate rapidly declined during the first 2 min of reperfusion. In contrast, nornicotine slowed post-ischemic succinate consumption, suggesting that electron backflow through complex I is the major pathway driving succinate consumption. Conclusions: Herein, we demonstrated that nornicotine was cardioprotective when delivered at early reperfusion in vitro and ex vivo. The mechanism of cardioprotection may be due to inhibition of rapid succinate consumption during early reperfusion via reverse electron flow back through complex I.

scholarly journals Correction: Control of mitochondrial superoxide production by reverse electron transport at complex I.

2019 ◽  
Vol 294 (19) ◽  
pp. 7966-7966
Author(s):  
Ellen L. Robb ◽  
Andrew R. Hall ◽  
Tracy A. Prime ◽  
Simon Eaton ◽  
Marten Szibor ◽  
...  
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Superoxide Production ◽  
Mitochondrial Superoxide ◽  
Reverse Electron Transport

scholarly journals Anesthesia-Sepsis-Associated Alterations in Liver Gene Expression Profiles and Mitochondrial Oxidative Phosphorylation Complexes

2020 ◽  
Vol 7 ◽  
Author(s):  
Hari Prasad Osuru ◽  
Umadevi Paila ◽  
Keita Ikeda ◽  
Zhiyi Zuo ◽  
Robert H. Thiele
Keyword(s):  
Gene Expression ◽  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Electron Transport Chain ◽  
Expression Profiles ◽  
Volatile Anesthetic ◽  
Heme Oxygenase 1 ◽  
Complex Ii ◽  
Transport Chain ◽  
The Impact

Background: Hepatic dysfunction plays a major role in adverse outcomes in sepsis. Volatile anesthetic agents may protect against organ dysfunction in the setting of critical illness and infection. The goal of this study was to study the impact of Sepsis-inflammation on hepatic subcellular energetics in animals anesthetized with both Propofol (intravenous anesthetic agent and GABA agonist) and Isoflurane (volatile anesthetic i.e., VAA).Methods: Sprague-Dawley rats were anesthetized with Propofol or isoflurane. Rats in each group were randomized to celiotomy and closure (control) or cecal ligation and puncture “CLP” (Sepsis-inflammation) for 8 h.Results: Inflammation led to upregulation in hepatic hypoxia-inducible factor-1 in both groups. Rats anesthetized with isoflurane also exhibited increases in bcl-2, inducible nitric oxide synthase, and heme oxygenase-1(HO-1) during inflammation, whereas rats anesthetized with Propofol did not. In rats anesthetized with isoflurane, decreased mRNA, protein (Complex II, IV, V), and activity levels (Complex II/III,IV,V) were identified for all components of the electron transport chain, leading to a decrease in mitochondrial ATP. In contrast, in rats anesthetized with Propofol, these changes were not identified after exposure to inflammation. RNA-Seq and real-time quantitative PCR (qPCR) expression analysis identified a substantial difference between groups (isoflurane vs. Propofol) in mitogen-activated protein kinase (MAPK) related gene expression following exposure to Sepsis-inflammation.Conclusions: Compared to rats anesthetized with Propofol, those anesthetized with isoflurane exhibit more oxidative stress, decreased oxidative phosphorylation protein expression, and electron transport chain activity and increased expression of organ-protective proteins.

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