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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
Open accessAbstract
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 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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“(27) identified small chemicals S1QELs as specific suppressors of superoxide production from the quinone reaction site in mammalian complex I during reverse electron transfer, although themechanism of their action in the enzyme was not disclosed.”
BackgroundS3QELs protect against diet‐induced intestinal barrier dysfunction
Watson, M. A., Pattavina, B., Hilsabeck, T. A. U., Lopez-Dominguez, J. A., Kapahi, P., & Brand, M. D. (2021) · Aging Cell · doi:10.1111/acel.13476 · Cited by 21
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“…antioxidant defenses such as MitoTEMPO, MitoQ, catechin, or KH176 (30, 41, 47, 53); (iii) mtROS site-specific suppressors such as S1Qel (7, 16, 67); (iv) transient inhibitors of respiratory chain complex I that act through S-nitrosation such as Mito-SNO (14, 66); and (v) regulators of…”
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“…of intrinsic mitochondrial oxidative defense: MitoTEMPO, MitoQ, catechin or KH176 [440 – 442], (iii) mtROS site-specific suppressors such as S1Qel [443,444], (iv) transient inhibitors of respiratory chain complex I that act through S-nitrosation such as Mito-SNO [427], and (v) regulators of…”
Diverse reaction behaviors of artificial ubiquinones in mitochondrial respiratory complex I
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“In this context, we previously showed that the mechanisms of action of S1QELs (suppressors of the superoxide production from the UQ reaction site in complex I, (49)) and IACS-010759 (a potent inhibitor of complex I of glycolysisdeficient hypoxic tumor cells, (50)) differ from those of traditional inhibitors and are di…”
ResultMnSOD non-acetylation mimic knock-in mice exhibit dilated cardiomyopathy
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“Previous work has screened several S1 and S3 analogs, which all have been shown to selectively interfere with mtH 2 O 2 production by complex I and complex III, respectively (3).”
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“One possibility is that the inefficiency of mitochondria in linking respiration to oxidative phosphorylation, due to the increase in proton leak, limits the production of reactive oxygen species (‘uncouple to survive’ hypothesis; Brand, 2000 ; Brand et al., 2016 ; Speakman et al., 2004 ).”
BackgroundThe oxidoreductase p66Shc acts as tumor suppressor in BRAFV 600E‐transformed cells
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“In contrast to other ROS-generating systems, p66Shc ablation did not interfere with normal cell survival (Giorgio et al., 2005), which was not the case for NOX-dependent ROS production or the inhibition of the electron transport chain (ETC) (Brand et al., 2016; Matsushima et al., 2013).”
BackgroundRegulation of Mitochondrial Quality Control of Intestinal Stem Cells in Homeostasis and Diseases
Lei, X., Xu, Z., Huang, Y., Huang, L., Lang, J., Qu, M., & Liu, D. (2024) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0489 · Cited by 7
Morton, K. S., George, A. J., & Meyer, J. N. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103538 · Cited by 7
“1 binds allosterically to CI and quenches superoxide anion production at the quinone binding site [72].”
InfluentialTargeted Redox Regulation α-Ketoglutarate Dehydrogenase Complex for the Treatment of Human Diseases
Mailloux, R. J. (2025) · Cells · doi:10.3390/cells14090653 · Cited by 7
Ying, G., Yu, J., Jiao, L., Liang, J., Wu, Z., Pan, B., Gao, S., Suhong, C., & Lv, G. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.121053 · Cited by 7
Qi, Y., Hu, M., Wang, Z., & Shang, W. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115725 · Cited by 7
Li, S., Wang, J., Andersen, J. V., Aldana, B. I., Zhang, B. X., Prochownik, E. V., & Rosenberg, P. A. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16205 · Cited by 7
Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation
González-Hernández, M., Gallardo-Andalucía, L., & Hernansanz‐Agustín, P. (2025) · Antioxidants and Redox Signaling · doi:10.1089/ars.2024.0737 · Cited by 7
“2B), as there is a debate on whether Q module or N module is responsible for the actual electron transfer to O 2 (Brand et al., 2016; Genova et al., 2001; Komlódi et al., 2018; Pryde and Hirst, 2011).”
Role of Mitochondrial ROS for Calcium Alternans in Atrial Myocytes
Oropeza‐Almazán, Y., & Blatter, L. A. (2024) · Biomolecules · doi:10.3390/biom14020144 · Cited by 7
Mitochondrial threshold for H2O2 release in skeletal muscle of mammals
Voituron, Y., Boël, M., & Roussel, D. (2020) · Mitochondrion · doi:10.1016/j.mito.2020.07.005 · Cited by 5
Gene therapy prevents onset of mitochondrial cardiomyopathy in neonatal mice with Ndufs6 deficiency
Zhang, X., Huang, L., Li, C., Yang, J., Duan, F., Su, Q., Zhang, Y., Kou, M., Zhou, X., Guo, L., et al. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02524-7 · Cited by 5
Alpha-ketoglutarate dehydrogenase: more than just a TCA cycle enzyme
Mailloux, R. J. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.02.050 · Cited by 5
Factors affecting liver mitochondrial hydrogen peroxide emission
Okoye, C. N., Chinnappareddy, N., Stevens, D., & Kamunde, C. (2022) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2022.110713 · Cited by 5
Qi, Y., Wang, Z., Zhang, Z., Yan, Y., Cheng, F., Feng, Y., Hou, Y., Zhou, L., Xu, Z., Xu, Z., et al. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117197 · Cited by 4
Fan, Z., Luo, P., Gao, Y., Ma, H., Fan, J., Sanan, S., Zhang, P., Lu, K., & Xia, H. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1618418 · Cited by 4
Pedriali, G., Leo, S., Tiezzi, M., Colarusso, E. N., Morciano, G., Tremoli, E., & Pinton, P. (2026) · Basic Research in Cardiology · doi:10.1007/s00395-026-01162-z · Cited by 5
Okoye, C. N., Chinnappareddy, N., Stevens, D., & Kamunde, C. (2021) · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology · doi:10.1016/j.cbpc.2021.109227 · Cited by 4
Respiratory complex I in mitochondrial membrane catalyzes oversized ubiquinones
Ikunishi, R., Otani, R., Masuya, T., Shinzawa‐Itoh, K., Shiba, T., Murai, M., & Miyoshi, H. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105001 · Cited by 5
“Contrary to the behavior expected for competitive inhibitors, the maximum inhibition of the electron transfer by some S1QELs is saturated at incomplete levels ( 30−80%) (28, 29, 52).”
BackgroundInfluentialOptimised measurement of mitochondrial respiratory capacity in frozen rat liver and heart
Knapton, A. E., O’Brien, K. A., Sowton, A. P., Armstrong, J. L., Davies, V., Kirk, C. M., McNally, B. D., Thackray, B. D., Holzner, L. M. W., & Murray, A. J. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.153405 · Cited by 3
Gonçalves, R. L. S., Wang, Z. B., Inouye, K., Lee, G. Y., Fu, X., Saksi, J., Rosique, C., Parlakgül, G., Arruda, A. P., Hui, S. T., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.21.528863 · Cited by 3
Mitochondrial Quality Control in Macrophages During Cardiovascular Disease
Falconer, R., & Day, E. A. (2026) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2026.02.034 · Cited by 2
The nuanced role of mitochondrial ROS in modulating aging and aging hallmarks
Müller-Eigner, A., Morin, E., Morton, K. S., & Wojtovich, A. P. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104319 · Cited by 2
“Collectively, these findings highlight the role of complex I-derived ROS to both age-related tissue dysfunction and acute cellular stress signaling [76,126].”
Semigolovskii, N. Y., Lobachenko, I. G., Симутис, И. С., Danilov, M. S., Yusupov, E., Ratnikov, V. A., Enkina, T. N., & Stelyukova, M. A. (2025) · Russian Journal of Cardiology and Cardiovascular Surgery · doi:10.17116/kardio202518021191 · Cited by 2
Development and Application of Activity-based Fluorescent Probes for High-Throughput Screening
Li, X., & Cheng, J. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867328666210525141728 · Cited by 3
Increased glycolysis is an early outcome of palmitate-mediated lipotoxicityPreprint
Kakimoto, P. A., Zorzano, A., & Kowaltowski, A. J. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.10.144808 · Cited by 2
Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammationPreprint
Peruzzotti‐Jametti, L., Willis, C. M., Hamel, R., Krzak, G., Reisz, J. A., Prag, H. A., Wu, V., Xiang, Y., van den Bosch, A. M. R., Nicaise, A. M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.03.574059 · Cited by 2
A mitochondrial redox switch licenses the onset of morphogenesis in animalsPreprint
Kahlon, U., Ricca, F. D., Pillai, S. J., Olivetta, M., Tharp, K. M., Jao, L.-E., Dudin, O., McDonald, K. L., & Aydogan, M. G. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.28.620733 · Cited by 2
Metabolic tuning facilitates nociceptor resilience to excitotoxicityPreprint
Yuan, L., Chandel, N. S., & Julius, D. J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.23.630176 · Cited by 2
Hypoxic preconditioning increases mitochondrial respiration and H2O2 production
Bergmeister, L., Doerrier, C., Fogli, B., Komlódi, T., Fischer, A., Springer, K., Schwarzer, C., & Gnaiger, E. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1628567 · Cited by 1
“Low levels of ROS contribute to the regulation of growth factor signaling, hypoxic responses, immune functions, and autophagy, however excessive ROS can cause oxidative harm (Reczek and Chandel, 2015; Azzi, 2022; Sies, 2020; Brand, 2016).”
Brand, M. D. (2025) · Biochemistry (Moscow) · doi:10.1134/s0006297925602527 · Cited by 2
“1 was found decrease ROS production by site I Q in mouse muscle mitochondria and to protect against ischemia-reperfusion injury in the perfused mouse heart [40], providing strong supporting evidence that ROS production from site I Q is a primary cause of cardiac ischemia-reperfusion injury.”
InfluentialSelf-citationMitochondrial electron transport chain modulation orchestrates divergent TLR3 and TLR7 responses
Sheridan, M.-E., Ahmed, D., Daraawi, M. A., Kovac, N., & Cassol, E. (2026) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiag034 · Cited by 1
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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