Inhibitors of ros production by the ubiquinone-binding site of mitochondrial complex i identified by chemical screening
Open accessAbstract
Mitochondrial production of reactive oxygen species is often considered an unavoidable consequence of aerobic metabolism and currently cannot be manipulated without perturbing oxidative phosphorylation. Antioxidants are widely used to suppress effects of reactive oxygen species after formation, but they can never fully prevent immediate effects at the sites of production. To identify site-selective inhibitors of mitochondrial superoxide/H2O2 production that do not interfere with mitochondrial energy metabolism, we developed a robust small-molecule screen and secondary profiling strategy. We describe the discovery and characterization of a compound (N-cyclohexyl-4-(4-nitrophenoxy)benzenesulfonamide; CN-POBS) that selectively inhibits superoxide/H2O2 production from the ubiquinone-binding site of complex I (site I(Q)) with no effects on superoxide/H2O2 production from other sites or on oxidative phosphorylation. Structure/activity studies identified a core structure that is important for potency and selectivity for site I(Q). By employing CN-POBS in mitochondria respiring on NADH-generating substrates, we show that site I(Q) does not produce significant amounts of superoxide/H2O2 during forward electron transport on glutamate plus malate. Our screening platform promises to facilitate further discovery of direct modulators of mitochondrially derived oxidative damage and advance our ability to understand and manipulate mitochondrial reactive oxygen species production under both normal and pathological conditions.
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Within mitochondria, the main sites of superoxide production are localized to electron transport chain complexes I and III.
“Within the mitochondria, the main sites of superoxide production have been localized to the electron transport chain (ETC) complexes I (C I) and Ⅲ [6–9].”
From Honokiol induces superoxide production by targeting mitochondrial respiratory chain complex I in Candida albicans (2017) · cites this paper as [8]
The Introduction identifies complexes I and III as having high capacities for superoxide/H2O2 production. But it also identifies at least ten mitochondrial production sites and says their contributions under normal conditions remain unknown, so it does not establish I and III as the main sites of production generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMost of the superoxide radicals generated by mitochondria are produced by complex I and complex III.
“There is growing evidence that most of the superoxide radicals generated by mitochondria is produced by C I and C Ⅲ[7,8].”
From Honokiol induces superoxide production by targeting mitochondrial respiratory chain complex I in Candida albicans (2017) · cites this paper as [8]
The Introduction (page not provided) says complexes I and III have high capacities for superoxide/H2O2 production. It does not establish that they produce most mitochondrial superoxide; it says the contribution of each site under normal circumstances remains unknown. (LLM, conf=0.86)
Experimental — accuracy not yet measuredC I exhibits only minimal ROS production with NADH-linked substrates, but addition of rotenone results in a significant increase in its rate.
“It is driven by NADH-linked substrates, C I exhibits only minimal ROS production, but the addition of a ubiquinone-site inhibitor, such as rotenone, results in a significant increase in its rate [7–9].”
From Honokiol induces superoxide production by targeting mitochondrial respiratory chain complex I in Candida albicans (2017) · cites this paper as [8]
During reverse electron transport driven by succinate, ROS production by C I is increased significantly and is inhibited by rotenone.
“During reverse electron transport, driven by succinate, ROS production by C I is increased significantly, and in this case, inhibited by the addition of rotenone [7, 8].”
From Honokiol induces superoxide production by targeting mitochondrial respiratory chain complex I in Candida albicans (2017) · cites this paper as [8]
Rotenone is a potent inducer of matrix mtROS generation and is widely used as a positive control for ROS probes targeted to the mitochondrial matrix, such as MitoSOX.
“Therefore, rotenone is a potent inducer of the generation of matrix mtROS and hence is widely used as positive control for ROS probes targeted to the mitochondrial matrix, such as MitoSOX [30,270,271].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [271]
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- Authors
- Orr, A. L., Ashok, D., Sarantos, M. R., Shi, T., Hughes, R. E., & Brand, M. D.
- Affiliations
- Buck Institute for Research on Aging (US)
- Corresponding author
- Orr, Adam L.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 65
- Pages
- 1047-1059
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC4321955
- OpenAlex
- W1968222122
- Cited by
- 80
- References
- 43
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 3 · 2016: 10 · 2015: 5 · 2014: 6
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation (SS-2288-09)
- National Institutes of Health (R01 AG033542, RL1 GM084432, TL1 AG032116)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- mitochondrial complex I, ubiquinone binding site, reactive oxygen species, superoxide, hydrogen peroxide, small molecule screening, structure-activity relationship, oxidative phosphorylation, mitochondrial electron transport chain, oxidative damage
- MeSH terms
- Animals, Binding Sites, Enzyme Inhibitors, Female, Mitochondria, Muscle, Oxidation-Reduction, Ubiquinone, Rats, Wistar, Reactive Oxygen Species, Electron Transport Complex I, Membrane Potential, Mitochondrial, High-Throughput Screening Assays
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