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The interplay between mitochondrial reactive oxygen species formation and the coenzyme Q reduction level.

ABSTRACT: Our aim was to elucidate the relationship between the rate of mitochondrial reactive oxygen species (mROS) formation and the reduction level of the mitochondrial coenzyme Q (mQ) pool under various levels of engagement of the mQ-reducing pathway (succinate dehydrogenase, complex II) and mQH₂-oxidizing pathways (the cytochrome pathway and alternative oxidase pathway, (AOX)) in mitochondria isolated from the amoeba Acanthamoeba castellanii. The mQ pool was shifted to a more reduced state by inhibition of mQH₂-oxidizing pathways (complex III and complex IV of the cytochrome pathway, and AOX) and the oxidative phosphorylation system. The mQ reduction level was lowered by decreasing the electron supply from succinate dehydrogenase and by stimulating the activity of the cytochrome or AOX pathways. The results indicate a direct dependence of mROS formation on the reduction level of the mQ pool for both mQH₂-oxidizing pathways. A higher mQ reduction level leads to a higher mROS formation. For the cytochrome pathway, mROS generation depends nonlinearly upon the mQ reduction level, with a stronger dependency observed at values higher than the mQ reduction level of the phosphorylating state (~?35%). AOX becomes more engaged at higher mQ pool reduction levels (above 40%), when mROS production via the cytochrome pathway increases. We propose that the mQ pool reduction level (endogenous mQ redox state) could be a useful endogenous reporter that allows indirect assessment of overall mROS production in mitochondria.

SUBMITTER: Dominiak K

PROVIDER: S-EPMC6078054 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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The interplay between mitochondrial reactive oxygen species formation and the coenzyme Q reduction level.

Dominiak Karolina K Koziel Agnieszka A Jarmuszkiewicz Wieslawa W

Redox biology 20180723

Our aim was to elucidate the relationship between the rate of mitochondrial reactive oxygen species (mROS) formation and the reduction level of the mitochondrial coenzyme Q (mQ) pool under various levels of engagement of the mQ-reducing pathway (succinate dehydrogenase, complex II) and mQH<sub>2</sub>-oxidizing pathways (the cytochrome pathway and alternative oxidase pathway, (AOX)) in mitochondria isolated from the amoeba Acanthamoeba castellanii. The mQ pool was shifted to a more reduced state ...[more]

PMID: 30059902

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Project description:BackgroundOxidative stress is causally linked to the progression of heart failure, and mitochondria are critical sources of reactive oxygen species in failing myocardium. We previously observed that in heart failure, elevated cytosolic Na(+) ([Na(+)](i)) reduces mitochondrial Ca(2+) ([Ca(2+)](m)) by accelerating Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger. Because the regeneration of antioxidative enzymes requires NADPH, which is indirectly regenerated by the Krebs cycle, and Krebs cycle dehydrogenases are activated by [Ca(2+)](m), we speculated that in failing myocytes, elevated [Na(+)](i) promotes oxidative stress.Methods and resultsWe used a patch-clamp-based approach to simultaneously monitor cytosolic and mitochondrial Ca(2+) and, alternatively, mitochondrial H(2)O(2) together with NAD(P)H in guinea pig cardiac myocytes. Cells were depolarized in a voltage-clamp mode (3 Hz), and a transition of workload was induced by beta-adrenergic stimulation. During this transition, NAD(P)H initially oxidized but recovered when [Ca(2+)](m) increased. The transient oxidation of NAD(P)H was closely associated with an increase in mitochondrial H(2)O(2) formation. This reactive oxygen species formation was potentiated when mitochondrial Ca(2+) uptake was blocked (by Ru360) or Ca(2+) efflux was accelerated (by elevation of [Na(+)](i)). In failing myocytes, H(2)O(2) formation was increased, which was prevented by reducing mitochondrial Ca(2+) efflux via the mitochondrial Na(+)/Ca(2+) exchanger.ConclusionsBesides matching energy supply and demand, mitochondrial Ca(2+) uptake critically regulates mitochondrial reactive oxygen species production. In heart failure, elevated [Na(+)](i) promotes reactive oxygen species formation by reducing mitochondrial Ca(2+) uptake. This novel mechanism, by which defects in ion homeostasis induce oxidative stress, represents a potential drug target to reduce reactive oxygen species production in the failing heart.

Dataset Information

The interplay between mitochondrial reactive oxygen species formation and the coenzyme Q reduction level.

Publications

The interplay between mitochondrial reactive oxygen species formation and the coenzyme Q reduction level.

Similar Datasets

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