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 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 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

Coenzyme Q Cytoprotective Mechanisms for Mitochondrial Complex I Cytopathies Involves NAD(P)H: Quinone Oxidoreductase 1(NQO1)

2002 ◽  
Vol 36 (4) ◽  
pp. 421-427 ◽  
Author(s):  
Tom S. Chan ◽  
Shirley Teng ◽  
John X. Wilson ◽  
Giuseppe Galati ◽  
Sumsallah Khan ◽  
...  
Keyword(s):  
Complex I ◽  
Coenzyme Q ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Quinone Oxidoreductase

scholarly journals The specificity of mitochondrial complex I for ubiquinones

1996 ◽  
Vol 313 (1) ◽  
pp. 327-334 ◽  
Author(s):  
Mauro ESPOSTI DEGLI ◽  
Anna NGO ◽  
Gabrielle L. McMULLEN ◽  
Anna GHELLI ◽  
Francesca SPARLA ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Electron Transport ◽  
Complex I ◽  
Reductase Activity ◽  
Redox Activity ◽  
Mitochondrial Complex I ◽  
Transport Activity ◽  
Mitochondrial Complex ◽  
Potential Generation ◽  
Electron Transport Activity

We report the first detailed study on the ubiquinone (coenzyme Q; abbreviated to Q) analogue specificity of mitochondrial complex I, NADH:Q reductase, in intact submitochondrial particles. The enzymic function of complex I has been investigated using a series of analogues of Q as electron acceptor substrates for both electron transport activity and the associated generation of membrane potential. Q analogues with a saturated substituent of one to three carbons at position 6 of the 2,3-dimethoxy-5-methyl-1,4-benzoquinone ring have the fastest rates of electron transport activity, and analogues with a substituent of seven to nine carbon atoms have the highest values of association constant derived from NADH:Q reductase activity. The rate of NADH:Q reductase activity is potently but incompletely inhibited by rotenone, and the residual rotenone-insensitive rate is stimulated by Q analogues in different ways depending on the hydrophobicity of their substituent. Membrane potential measurements have been undertaken to evaluate the energetic efficiency of complex I with various Q analogues. Only hydrophobic analogues such as nonyl-Q or undecyl-Q show an efficiency of membrane potential generation equivalent to that of endogenous Q. The less hydrophobic analogues as well as the isoprenoid analogue Q-2 are more efficient as substrates for the redox activity of complex I than for membrane potential generation. Thus the hydrophilic Q analogues act also as electron sinks and interact incompletely with the physiological Q site in complex I that pumps protons and generates membrane potential.

scholarly journals Coenzyme Q1 redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia

2008 ◽  
Vol 105 (4) ◽  
pp. 1114-1126 ◽  
Author(s):  
Said H. Audi ◽  
Marilyn P. Merker ◽  
Gary S. Krenz ◽  
Taniya Ahuja ◽  
David L. Roerig ◽  
...  
Keyword(s):  
Pulmonary Circulation ◽  
Complex I ◽  
Dominant Role ◽  
Coenzyme Q ◽  
Redox Status ◽  
Complex Iii ◽  
Mitochondrial Complex ◽  
Quinone Oxidoreductase ◽  
Arterial Inflow ◽  
Complex I Activity

The objective was to evaluate the pulmonary disposition of the ubiquinone homolog coenzyme Q1 (CoQ1) on passage through lungs of normoxic (exposed to room air) and hyperoxic (exposed to 85% O2 for 48 h) rats. CoQ1 or its hydroquinone (CoQ1H2) was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of CoQ1H2 and CoQ1 were measured. CoQ1H2 appeared in the venous effluent when CoQ1 was infused, and CoQ1 appeared when CoQ1H2 was infused. In normoxic lungs, CoQ1H2 efflux rates when CoQ1 was infused decreased by 58 and 33% in the presence of rotenone (mitochondrial complex I inhibitor) and dicumarol [NAD(P)H-quinone oxidoreductase 1 (NQO1) inhibitor], respectively. Inhibitor studies also revealed that lung CoQ1H2 oxidation was via mitochondrial complex III. In hyperoxic lungs, CoQ1H2 efflux rates when CoQ1 was infused decreased by 23% compared with normoxic lungs. Based on inhibitor effects and a kinetic model, the effect of hyperoxia could be attributed predominantly to 47% decrease in the capacity of complex I-mediated CoQ1 reduction, with no change in the other redox processes. Complex I activity in lung homogenates was also lower for hyperoxic than for normoxic lungs. These studies reveal that lung complexes I and III and NQO1 play a dominant role in determining the vascular concentration and redox status of CoQ1 during passage through the pulmonary circulation, and that exposure to hyperoxia decreases the overall capacity of the lung to reduce CoQ1 to CoQ1H2 due to a depression in complex I activity.

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