Robb, EL;
Hall, AR;
Prime, TA;
Eaton, S;
Szibor, M;
Viscimo, C;
James, AM;
(2018)
Control of mitochondrial superoxide production by reverse electron transport at complex I.
Journal of Biological Chemistry
, 293
(25)
pp. 9869-9879.
10.1074/jbc.RA118.003647.
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Abstract
The generation of mitochondrial superoxide (O2̇̄) by reverse electron transport (RET) at complex I causes oxidative damage in pathologies such as ischemia reperfusion injury, but also provides the precursor to H2O2 production in physiological mitochondrial redox signaling. Here, we quantified the factors that determine mitochondrial O2̇̄ production by RET in isolated heart mitochondria. Measuring mitochondrial H2O2 production at a range of proton-motive force (Δp) values and for several coenzyme Q (CoQ) and NADH pool redox states obtained with the uncoupler p-trifluoromethoxyphenylhydrazone, we show that O2̇̄ production by RET responds to changes in O2 concentration, the magnitude of Δp, and the redox states of the CoQ and NADH pools. Moreover, we determined how expressing the alternative oxidase from the tunicate Ciona intestinalis to oxidize the CoQ pool affected RET-mediated O2̇̄ production at complex I, underscoring the importance of the CoQ pool for mitochondrial O2̇̄ production by RET. An analysis of O2̇̄ production at complex I as a function of the thermodynamic forces driving RET at complex I revealed that many molecules that affect mitochondrial reactive oxygen species production do so by altering the overall thermodynamic driving forces of RET, rather than by directly acting on complex I. These findings clarify the factors controlling RET-mediated mitochondrial O2̇̄ production in both pathological and physiological conditions. We conclude that O2̇̄ production by RET is highly responsive to small changes in Δp and the CoQ redox state, indicating that complex I RET represents a major mode of mitochondrial redox signaling.
| Type: | Article |
|---|---|
| Title: | Control of mitochondrial superoxide production by reverse electron transport at complex I |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.RA118.003647 |
| Publisher version: | https://doi.org/10.1074/jbc.RA118.003647 |
| Language: | English |
| Additional information: | Copyright © 2018 Robb et al. Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0). |
| Keywords: | mitochondria, mitochondrial membrane potential, redox signaling, reactive oxygen species (ROS), respiration, complex I, reverse electron transport, RET, coenzyme Q, superoxide |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10048048 |
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