Suppressors of Superoxide-H 2 O 2 Production at Site I Q of Mitochondrial Complex I Protect against Stem Cell Hyperplasia and Ischemia-Reperfusion Injury
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Using high-throughput screening we identified small molecules that suppress superoxide and/or H 2 O 2 production during reverse electron transport through mitochondrial respiratory complex I (site I Q) without affecting oxidative phosphorylation (suppressors of site I Q electron leak, "S1QELs"). S1QELs diminished endogenous oxidative damage in primary astrocytes cultured at ambient or low oxygen tension, showing that site I Q is a normal contributor to mitochondrial superoxide-H 2 O 2 production in cells. They diminished stem cell hyperplasia in Drosophila intestine in vivo and caspase activation in a cardiomyocyte cell model driven by endoplasmic reticulum stress, showing that superoxide-H 2 O 2 production by site I Q is involved in cellular stress signaling. They protected against ischemia-reperfusion injury in perfused mouse heart, showing directly that superoxide-H 2 O 2 production by site I Q is a major contributor to this pathology. S1QELs are tools for assessing the contribution of site I Q to cell physiology and pathology and have great potential as therapeutic leads.
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Complex II is capable of matrix mtROS production.
“Complex II is also capable of matrix mtROS production [100,101,102,103,104] and two different modes of production were described:”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [102]
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“This could be done by stopping oxidation of succinate with malonates [69,70], or by adding compounds that interact with the respiratory chain to decrease ROS production, such as S1QELs [71], or the mitochondria-targeted S-nitrosating agent MitoSNO [72–74].”
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Small-Molecule Inhibitors of Reactive Oxygen Species Production
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BackgroundCoenzyme Q10: Novel Formulations and Medical Trends
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BackgroundInfluentialSelf-citationReactive Oxygen Species in intestinal stem cell metabolism, fate and function
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Self-citationNDP52 acts as a redox sensor in PINK1/Parkin‐mediated mitophagy
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“To test this, we used S1QEL and S3QEL to suppress ROS production by Complex I and III, respectively (Brand et al, 2016).”
MethodFang, J., Wong, H. S., & Brand, M. D. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101722 · Cited by 64 · see citing works
“Suppressors of site IQ electron leak (S1QELs) and suppressors of site IIIQo electron leak (S3QELs) [8–10] specifically suppress production of superoxide/hydrogen peroxide from site IQ and site IIIQo, respectively, without inhibiting electron transport, affecting oxidative phosphorylation, or causing cytotoxicity at th…”
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“H2O2 can be generated as a consequence of electron leak from one of ten sites within the ETC (Brand, 2016; Brand et al., 2016; Orr et al., 2015; Quinlan et al., 2013).”
BackgroundSelf-citationReverse electron transfer is activated during aging and contributes to aging and age‐related disease
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“1(1 μ M) [18,19], or S3QEL-2 (3.3 μ M) [61], from 100x stocks in DMSO.”
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“We blocked mitochondrial ROS production from sites on complexes I and III of the ETC using previously characterized compounds (Brand et al., 2016; Orr et al., 2013) but did not see any effect on Mtk induction after mitochondrial stress (Figure 1—figure supplement 3a).”
Self-citationPotential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic β -cells
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“3B) ( 26 ).”
Current perspectives of mitochondria-targeted antioxidants in cancer prevention and treatment
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“Suppressors of ROS production in the IQ site (upstream of the quinone-binding rotenone-sensitive site) in complex I (S1QEL) suppress ROS production in various cell models and protect against ischemia-reperfusion injury in the perfused mouse heart (Brand et al., 2016).”
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“…in high-risk windows, reinforce mitochondrial quality control (biogenesis and mitophagy to cull ROS-prone organelles) and buffer Ca²⁺ transfer at MAMs to prevent feed-forward ROS/Ca²⁺ loops—favoring these node-and compartment-specific levers over blanket antioxidant suppression (Brand et al. 2016).”
An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals
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“Another compound also inhibiting mitochondrial complex I ROS production, N-cyclohexyl-4-(4-nitrophenoxy) benzenesulfonamide, has very recently been described by Brand’s group [7] along with other molecules [38, 39].”
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Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis
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The role of mitochondrial reactive oxygen species in insulin resistance
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Self-citationNAD Depletion Mediates Cytotoxicity in Human Neurons With Autophagy Deficiency
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“1, an antioxidant that suppresses mitoROS via RET (43), decreased TNF-a and IL-1b production by BMDMs exposed to swollen conidia.”
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Self-citationOxidation of retromer complex controls mitochondrial translation
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“Interestingly, while probing superoxide formation sites with suppressors of electron leak at the specific Complex I or Complex III ubiquinone-binding sites (9), the S3QEL suppressor diminished superoxide release into the mitochondrial matrix more intensively with increased glucose (down to *40% at 25 mM glucose).”
BackgroundReverse Electron Transfer by Respiratory Complex I Catalyzed in a Modular Proteoliposome System
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InfluentialSelf-citation
- Authors
- Brand, M. D., Goncalves, R. L. S., Orr, A. L., Vargas, L., Gerencser, A. A., Borch Jensen, M., Wang, Y. T., Melov, S., Turk, C. N., Matzen, J. T., Dardov, V. J., Petrassi, H. M., Meeusen, S. L., Perevoshchikova, I. V., Jasper, H., Brookes, P. S., & Ainscow, E. K.
- Affiliations
- Buck Institute for Research on Aging (US)
- Genomics Institute of the Novartis Research Foundation (US)
- University of Rochester Medicine (US)
- Corresponding author
- Brand, Martin D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 24
- Issue
- 4
- Pages
- 582-592
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5061631
- OpenAlex
- W2522162634
- Cited by
- 228
- References
- 35
- Citations by year
- 2026: 22 · 2025: 25 · 2024: 26 · 2023: 23 · 2022: 23 · 2021: 31 · 2020: 29 · 2019: 20 · 2018: 15 · 2017: 14
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG033542, TL1AG032116)
- National Heart, Lung, and Blood Institute (R01HL127891)
- National Institute of General Medical Sciences (R01GM100196)
- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial complex I, reverse electron transfer, superoxide production, hydrogen peroxide production, electron leak, small molecule screening, intestinal stem cells, Drosophila intestine, endoplasmic reticulum stress, caspase activation, cardiomyocytes, ischemia-reperfusion injury, heart, astrocytes, oxidative stress
- MeSH terms
- Animals, Astrocytes, Cells, Cultured, Drosophila, Heart, Hydrogen Peroxide, Hyperplasia, Intestines, Mitochondria, Muscle, Oxidative Phosphorylation, Perfusion, Stem Cells, Superoxides, Tunicamycin, Reperfusion Injury, Oxidative Stress, Cytoprotection, Electron Transport Complex I, Cell Proliferation, Mice, Rats, Caspase 3, Caspase 7
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