S1QELs suppress mitochondrial superoxide/hydrogen peroxide production from site IQ without inhibiting reverse electron flow through Complex I

Wong, Hoi-Shan; Monternier, Pierre‐Axel; Brand, Martin D.

doi:10.1016/j.freeradbiomed.2019.09.006

Cited by 32 publications

(31 citation statements)

References 53 publications

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“…To explain the direction-dependent and incomplete (maximally ~30−80%) inhibition of electron transfer by S1QELs, we previously proposed that S1QELs do not occupy the binding cavity for ubiquinone; rather, they may indirectly affect the ubiquinone redox reactions by inducing structural changes of the cavity through binding to the middle of the ND1 subunit (29). Wong et al (39) recently reported that the binding of S1QELs to complex I in rat skeletal muscle mitochondria (at concentrations exhibiting no electron transfer inhibition) influences conformation of the binding sites for rotenone and piericidin A, resulting in a decrease in the inhibitory potencies of both inhibitors. On the basis of comprehensive interpretations of the present results, it is likely that IACS-010759 also indirectly affects the ubiquinone redox reactions by binding to the ND1 subunit.…”

Section: Discussionmentioning

confidence: 99%

IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism

Tsuji

Akao

Masuya

et al. 2020

Journal of Biological Chemistry

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The small molecule IACS-010759 has been reported to potently inhibit the proliferation of glycolysis-deficient hypoxic tumor cells by interfering with the functions of mitochondrial NADH-ubiquinone oxidoreductase (complex I) without exhibiting cytotoxicity at tolerated doses in normal cells. Considering the significant cytotoxicity of conventional quinone-site inhibitors of complex I, such as piericidin and acetogenin families, we hypothesized that the mechanism of action of IACS-010759 on complex I differs from that of other known quinone-site inhibitors. To test this possibility, here we investigated IACS-010759's mechanism in bovine heart submitochondrial particles. We found that IACS-010759, like known quinone-site inhibitors, suppresses chemical modification by the tosyl reagent AL1 of Asp160 in the 49-kDa subunit, located deep in the interior of a previously proposed quinone-access channel. However, contrary to the other inhibitors, IACS-010759 direction-dependently inhibited forward and reverse electron transfer and did not suppress binding of the quinazoline-type inhibitor [125I]AzQ to the N terminus of the 49-kDa subunit. Photoaffinity labeling experiments revealed that the photoreactive derivative [125I]IACS-010759-PD1 binds to the middle of the membrane subunit ND1 and that inhibitors that bind to the 49-kDa or PSST subunit cannot suppress the binding. We conclude that IACS-010759's binding location in complex I differs from that of any other known inhibitor of the enzyme. Our findings, along with those from previous study, reveal that the mechanisms of action of complex I inhibitors with widely different chemical properties are more diverse than can be accounted for by the quinone-access channel model proposed by structural biology studies.

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Section: Discussionmentioning

confidence: 99%

IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism

Tsuji

Akao

Masuya

et al. 2020

Journal of Biological Chemistry

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“…At least eleven distinct sites in the mitochondrial electron transport chain and associated substrate dehydrogenases have been characterized and shown to generate superoxide or hydrogen peroxide at measurable rates using isolated mitochondria. The characteristics of these sites are reviewed elsewhere (Brand et al 2004;Brand 2010;Quinlan et al 2013;Brand 2016;Wong et al 2017Wong et al , 2019. Each site generates superoxide on the matrix side of the mitochondrial inner membrane, or within the matrix itself, and some of them may also generate hydrogen peroxide as the primary product.…”

Section: Sites Of Mitochondrial Production Of Superoxide and Hydrogenmentioning

confidence: 99%

“…S1QELs (Brand et al 2016) and S3QELs (Orr et al 2015) are small molecules that suppress electron leak from the respiratory chain to oxygen to form superoxide and hydrogen peroxide at sites I Q and III Qo , respectively. Importantly, they do so without inhibiting forward or reverse electron transport in the respiratory chain (Wong et al 2019) and without inhibiting oxidative phosphorylation. Measurement of the acute effects of S1QELs and S3QELs on total cellular hydrogen peroxide production has enabled extension of these ex vivo observations (Goncalves et al 2015(Goncalves et al , 2020 to intact cells and organisms, and has shown that sites I Q and III Qo dominate the mitochondrial contribution to cytosolic hydrogen peroxide levels in cultured C2C12 myoblasts and myocytes (Wong et al 2018;Goncalves et al 2020).…”

Section: Sites Of Mitochondrial Production Of Superoxide and Hydrogenmentioning

confidence: 99%

Riding the tiger – physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix

Brand

2020

Critical Reviews in Biochemistry and Molecular Biology

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Elevated mitochondrial matrix superoxide and/or hydrogen peroxide concentrations drive a wide range of physiological responses and pathologies. Concentrations of superoxide and hydrogen peroxide in the mitochondrial matrix are set mainly by rates of production, the activities of superoxide dismutase-2 (SOD2) and peroxiredoxin-3 (PRDX3), and by diffusion of hydrogen peroxide to the cytosol. These considerations can be used to generate criteria for assessing whether changes in matrix superoxide or hydrogen peroxide are both necessary and sufficient to drive redox signaling and pathology: is a phenotype affected by suppressing superoxide and hydrogen peroxide production; by manipulating the levels of SOD2, PRDX3 or mitochondria-targeted catalase; and by adding mitochondria-targeted SOD/catalase mimetics or mitochondria-targeted antioxidants? Is the pathology associated with variants in SOD2 and PRDX3 genes? Filtering the large literature on mitochondrial redox signaling using these criteria highlights considerable evidence that mitochondrial superoxide and hydrogen peroxide drive physiological responses involved in cellular stress management, including apoptosis, autophagy, propagation of endoplasmic reticulum stress, cellular senescence, HIF1a signaling, and immune responses. They also affect cell proliferation, migration, differentiation, and the cell cycle. Filtering the huge literature on pathologies highlights strong experimental evidence that 30-40 pathologies may be driven by mitochondrial matrix superoxide or hydrogen peroxide. These can be grouped into overlapping and interacting categories: metabolic, cardiovascular, inflammatory, and neurological diseases; cancer; ischemia/reperfusion injury; aging and its diseases; external insults, and genetic diseases. Understanding the involvement of mitochondrial matrix superoxide and hydrogen peroxide concentrations in these diseases can facilitate the rational development of appropriate therapies.

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“…For example, RET would be highly sensitive to uncouplers and malonate (to block ubiquinol production). To disambiguate the exact site (s), then selective inhibitors of mitochondrial superoxide production at complex I and complex III termed S1QEL and S3QEL, respectively, would be useful [ 150 , 151 , 152 , 153 ] (see Box 2 ). Unlike respiratory chain inhibitors (e.g., rotenone), S1QEL/S3QEL seem to selectively block superoxide production without terminally arresting electron transfer, which could make it possible to infer native sites.…”

Section: How Mitochondria Produce Superoxide In Art: the Unknownmentioning

confidence: 99%

Mechanisms of Mitochondrial ROS Production in Assisted Reproduction: The Known, the Unknown, and the Intriguing

Cobley

2020

Antioxidants

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The consensus that assisted reproduction technologies (ART), like in vitro fertilization, to induce oxidative stress (i.e., the known) belies how oocyte/zygote mitochondria—a major presumptive oxidative stressor—produce reactive oxygen species (ROS) with ART being unknown. Unravelling how oocyte/zygote mitochondria produce ROS is important for disambiguating the molecular basis of ART-induced oxidative stress and, therefore, to rationally target it (e.g., using site-specific mitochondria-targeted antioxidants). I review the known mechanisms of ROS production in somatic mitochondria to critique how oocyte/zygote mitochondria may produce ROS (i.e., the unknown). Several plausible site- and mode-defined mitochondrial ROS production mechanisms in ART are proposed. For example, complex I catalyzed reverse electron transfer-mediated ROS production is conceivable when oocytes are initially extracted due to at least a 10% increase in molecular dioxygen exposure (i.e., the intriguing). To address the term oxidative stress being used without recourse to the underlying chemistry, I use the species-specific spectrum of biologically feasible reactions to define plausible oxidative stress mechanisms in ART. Intriguingly, mitochondrial ROS-derived redox signals could regulate embryonic development (i.e., their production could be beneficial). Their potential beneficial role raises the clinical challenge of attenuating oxidative damage while simultaneously preserving redox signaling. This discourse sets the stage to unravel how mitochondria produce ROS in ART, and their biological roles from oxidative damage to redox signaling.

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S1QELs suppress mitochondrial superoxide/hydrogen peroxide production from site IQ without inhibiting reverse electron flow through Complex I

Cited by 32 publications

References 53 publications

IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism

IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism

Riding the tiger – physiological and pathological effects of superoxide and hydrogen peroxide generated in the mitochondrial matrix

Mechanisms of Mitochondrial ROS Production in Assisted Reproduction: The Known, the Unknown, and the Intriguing

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