The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijević, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N. J., Smith, A. C., et al. (2014) · Nature · doi:10.1038/nature13909 · Cited by 2,907
Self-citationMitochondrial ROS Signaling in Organismal Homeostasis
Shadel, G. S., & Horvath, T. L. (2015) · Cell · doi:10.1016/j.cell.2015.10.001 · Cited by 1,353
The sites and topology of mitochondrial superoxide production
Brand, M. D. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.01.003 · Cited by 1,217
Self-citationBrand, M. D. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.001 · Cited by 1,063
Self-citationMosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development
Lee, T., & Luo, L. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01791-4 · Cited by 928
Role of Metabolic H2O2 Generation
Sies, H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r113.544635 · Cited by 761
A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury
Chouchani, E. T., Pell, V. R., James, A. M., Work, L. M., Saeb-Parsy, K., Frezza, C., Krieg, T., & Murphy, M. P. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.009 · Cited by 752
Sites of reactive oxygen species generation by mitochondria oxidizing different substrates
Quinlan, C. L., Perevoshchikova, I. V., Hey‐Mogensen, M., Orr, A. L., & Brand, M. D. (2013) · Redox Biology · doi:10.1016/j.redox.2013.04.005 · Cited by 608
Self-citationJNK Activity in Somatic Stem Cells Causes Loss of Tissue Homeostasis in the Aging Drosophila Gut
Biteau, B., Hochmuth, C. E., & Jasper, H. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.07.024 · Cited by 583
Self-citationMitochondrial disease in superoxide dismutase 2 mutant mice
Melov, S., Coskun, P., Patel, M., Tuinstra, R., Cottrell, B., Jun, A. S., Zastawny, T. H., Dizdaroglu, M., Goodman, S. I., Huang, T.-T., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.3.846 · Cited by 581
Self-citation
Cited by
Sorted by citations
Reactive oxygen species (ROS) as pleiotropic physiological signalling agents
Sies, H., & Jones, D. P. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0230-3 · Cited by 5,335
Sies, H. (2017) · Redox Biology · doi:10.1016/j.redox.2016.12.035 · Cited by 2,148
Redox metabolism: ROS as specific molecular regulators of cell signaling and function
Lennicke, C., & Cochemé, H. M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.018 · Cited by 1,313
Mitochondrial dysfunction: mechanisms and advances in therapy
Yao, Z., Li, H., Liao, P., Chen, L., Pan, Y., Zheng, Y., Zhang, C., Liu, D., Zheng, M., & Gao, J. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01839-8 · Cited by 1,382
Mitochondria as a therapeutic target for common pathologies
Murphy, M. P., & Hartley, R. C. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.174 · Cited by 846
Functions of ROS in Macrophages and Antimicrobial Immunity
Herb, M., & Schramm, M. (2021) · Antioxidants · doi:10.3390/antiox10020313 · Cited by 633
Bordt, E. A., Clerc, P., Roelofs, B. A., Saladino, A. J., Tretter, L., Ádám‐Vizi, V., Cherok, E., Khalil, A., Yadava, N., Ge, S. X., et al. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.02.020 · Cited by 605
“Succinate accumulates during ischemia and is oxidized rapidly during reperfusion, producing ROS by RET that contribute to injury (Chouchani et al., 2014; Brand et al., 2016).”
BackgroundAccumulation of succinate controls activation of adipose tissue thermogenesis
Mills, E. L., Pierce, K. A., Jedrychowski, M. P., Garrity, R., Winther, S., Vidoni, S., Yoneshiro, T., Spinelli, J. B., Lu, G. Z., Kazak, L., et al. (2018) · Nature · doi:10.1038/s41586-018-0353-2 · Cited by 539
Scialò, F., Fernández-Ayala, D. J., & Sanz, A. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00428 · Cited by 517
“Following this logic, Martin Brand’s group has started to design antioxidants that target ROS produced exclusively by CI (Brand et al., 2016) or CIII (Orr et al., 2015).”
BackgroundMethodInfluentialNeuroprotective Effect of Antioxidants in the Brain
Lee, K. H., Cha, M., & Lee, B. H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197152 · Cited by 543
Wong, H. S., Dighe, P. A., Mezera, V., Monternier, P., & Brand, M. D. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.789271 · Cited by 493
“production from site IQ in primary astrocytes under an unstressed condition (74).”
BackgroundSelf-citationMitochondrial iron–sulfur clusters: Structure, function, and an emerging role in vascular biology
Read, A. D., Bentley, R. E. T., Archer, S. L., & Dunham‐Snary, K. J. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102164 · Cited by 440
“A new generation of antioxidants that are capable of suppressing electron leak specifically from the IQ site have been shown to protect against ischaemia-reperfusion injury in in vitro modeling of cardiac I/R, providing further evidence of RET-induced ROS production during reperfusion and providing new therapeutic lea…”
BackgroundGeneration of Reactive Oxygen Species by Mitochondria
Hernansanz‐Agustín, P., & Enrı́quez, J. A. (2021) · Antioxidants · doi:10.3390/antiox10030415 · Cited by 424
“Notably, the exact site of ROS production by RET is not yet clear as some authors propose that it occurs at the flavin site of CI (CIN; [36,39,40]), whereas others suggest the ubiquinone-binding site of CI (CIQ) plus CIN [41,42] or the iron-sulphur cluster N2 [43] as the main actors.”
BackgroundIschemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies
Soares, R. O. D. S., Losada, D. M., Jordani, M. C., Évora, P. R. B., & Castro-e-Silva, O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205034 · Cited by 427
Mitochondrial control of immunity: beyond ATP
Mehta, M., Weinberg, S. E., & Chandel, N. S. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.66 · Cited by 409
The role of mitochondrial ROS in the aging brain
Stefanatos, R., & Sanz, A. (2018) · FEBS Letters · doi:10.1002/1873-3468.12902 · Cited by 358
“Finally, novel antioxidant molecules that prevent electron leak from specific sites within the respiratory complexes have been developed and tested in human cells as well as mouse and fly models [15, 16].”
BackgroundMitochondrial complex I ROS production and redox signaling in hypoxia
Okoye, C. N., Koren, S. A., & Wojtovich, A. P. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102926 · Cited by 342
Superoxide Radicals in the Execution of Cell Death
Fujii, J., Homma, T., & Osaki, T. (2022) · Antioxidants · doi:10.3390/antiox11030501 · Cited by 337
Role of mitochondria in the mechanism(s) of action of metformin
Vial, G., Detaille, D., & Guigas, B. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00294 · Cited by 303
“In line with this, a new generation of oxidative stress inhibitors that specifically neutralize ROS produced via RET at the IQ site within complex 1 has been shown to lower oxidative damage, inhibit cellular stress signaling and protect against ischemia-reperfusion heart injury (41).”
BackgroundCadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism
Yan, L., & Allen, D. C. (2021) · Biomolecules · doi:10.3390/biom11111575 · Cited by 297
Mitochondria as a therapeutic target for ischemic stroke
He, Z., Ning, N., Zhou, Q., Khoshnam, S. E., & Farzaneh, M. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.11.005 · Cited by 272
Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man
Sinenko, S. A., Starkova, T. Y., Kuzmin, A. A., & Tomilin, A. N. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.714370 · Cited by 267
Mitochondrial complex I activity in microglia sustains neuroinflammation
Peruzzotti-Jametti, L., Willis, C. M., Krzak, G., Hamel, R., Pirvan, L., Ionescu, R.-B., Reisz, J. A., Prag, H. A., Garcia-Segura, M. E., Wu, V., et al. (2024) · Nature · doi:10.1038/s41586-024-07167-9 · Cited by 239
Oncogenic pathways and the electron transport chain: a dangeROS liaison
Raimondi, V., Ciccarese, F., & Ciminale, V. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0651-y · Cited by 232
“rotenone and dimethyl-malonate, respectively), as well as antioxidants, protect the heart from ischaemia/reperfusionmediated tissue damage.(106,111) Although the role of RET in cancer has not been directly investigated, it is now clear that oxygen tension in the tumour microenvironment is subjected to ample temporal a…”
BackgroundDesigning Stimuli‐Responsive Upconversion Nanoparticles that Exploit the Tumor Microenvironment
Ovais, M., Mukherjee, S., Pramanik, A., Das, D., Mukherjee, A., Raza, A., & Chen, C. (2020) · Advanced Materials · doi:10.1002/adma.202000055 · Cited by 218
A Cellular Mechanism to Detect and Alleviate Reductive Stress
Manford, A. G., Rodríguez-Pérez, F., Shih, K. Y., Shi, Z., Berdan, C. A., Choe, M., Titov, D. V., Nomura, D. K., & Rapé, M. (2020) · Cell · doi:10.1016/j.cell.2020.08.034 · Cited by 205
“Scavengers of mitochondrion-derived ROS, which impose reductive stress by chemical means (Banba et al., 2019; Brand et al., 2016; Orr et al., 2015), also inhibited myoblast differentiation (Figure 1G).”
BackgroundRegulation of redox balance in cancer and T cells
Kong, H., & Chandel, N. S. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000257 · Cited by 182
“Importantly, such a phenotype is rescued by exogenous H2O2, whereas wildtype T cells treated with a mitochondria-targeted antioxidant mimic the complex III-deficient T cells.”
BackgroundInfluentialCytoplasmic and Mitochondrial NADPH-Coupled Redox Systems in the Regulation of Aging
Bradshaw, P. C. (2019) · Nutrients · doi:10.3390/nu11030504 · Cited by 178
Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance
Fazakerley, D. J., Chaudhuri, R., Yang, P., Maghzal, G. J., Thomas, K. C., Krycer, J. R., Humphrey, S. J., Parker, B. L., Fisher-Wellman, K. H., Meoli, C. C., et al. (2018) · eLife · doi:10.7554/elife.32111 · Cited by 160
“Recent chemical screens have successfully identified compounds that prevent superoxide production from complex I (Brand et al., 2016) and III (Orr et al., 2015), without impairing electron transport.”
BackgroundMitochondria reactive oxygen species signaling in immune responses
Weinberg, S. E., & Chandel, N. S. (2025) · Immunity · doi:10.1016/j.immuni.2025.07.012 · Cited by 175
A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering
To, T., Cuadros, A. M., Shah, H., Hung, W. H. W., Yang, L., Kim, S. H., Rubin, D. H. F., Boe, R. H., Rath, S. P., Eaton, J. K., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.032 · Cited by 141
“Furthermore, administration of antioxidants, including the specific complex I-RET inhibitor S1QEL (Brand et al., 2016), does not suppress oligomycin’s toxicity (Figure S5F).”
BackgroundZhang, J., Simpson, C. M., Berner, J., Chong, H. B., Fang, J., Ordulu, Z., Weiss‐Sadan, T., Possemato, A. P., Harry, S. A., Takahashi, M., et al. (2023) · Cell · doi:10.1016/j.cell.2023.04.026 · Cited by 149
Metformin targets mitochondrial electron transport to reduce air-pollution-induced thrombosis
Soberanes, S., Misharin, A. V., Jairaman, A., Morales-Nebreda, L., McQuattie-Pimentel, A. C., Cho, T., Hamanaka, R. B., Meliton, A. Y., Reyfman, P. A., Walter, J. M., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.019 · Cited by 131
“In contrast, S1QEL, a suppressor of superoxide production from mitochondrial complex I identified in a similar screen, failed to prevent PM-induced ROS generation or IL-6 release (Figures 2D and 2E) (Brand et al., 2016).”
BackgroundMitochondria as a therapeutic target for cardiac ischemia‑reperfusion injury (Review)
Marin, W., Marin, D., Ao, X., & Liu, Y. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4823 · Cited by 140
“Suppressors of site IQ electron leak (S1QELs), S1QELs 1.1‑1.6 and S1QELs 2.2‑2.4, can inhibit ROS production at complex I during reverse electron transport without altering basal respiration or the resting OXPHOS.”
BackgroundInfluentialExercise and mitochondrial dynamics: keeping in shape with ROS and AMPK
Trewin, A., Berry, B., & Wojtovich, A. (2018) · Antioxidants · doi:10.3390/antiox7010007 · Cited by 129
“Recently, Brand and colleagues have developed small molecules which bind with high specificity to complex I and III (known as Suppressors of site IQ and IIIQo Electron Leak—S1QEL and S3QEL, respectively) [140,141].”
BackgroundROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak
Debattisti, V., Gerencser, A. A., Saotome, M., Das, S., & Hajnóczky, G. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.060 · Cited by 132
“, 2016) and on the involvement of mitochondrial respiratory complex I- and III-originated ROS in ER-stress-induced caspase activation (Brand et al., 2016), a Ca-induced rise in mitochondrial ROS could serve as a signal to stop mitochondria in proximity to ER to establish new contact sites to serve as signaling modulat…”
Self-citationMitochondrial function and gastrointestinal diseases
Haque, P. S., Kapur, N., Barrett, T. A., & Theiss, A. L. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00931-2 · Cited by 146
“2) inhibited Drosophila ISC proliferation via dampening of mtROS 76 .”
Brand, M. D. (2020) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2020.1828258 · Cited by 123
Self-citationMitochondrial calcium and reactive oxygen species in cardiovascular disease
Murphy, E., & Liu, J. C. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvac134 · Cited by 123
Integrated Stress Response Couples Mitochondrial Protein Translation With Oxidative Stress Control
Zhang, G., Wang, X., Li, C., Li, Q., An, Y. A., Luo, X., Deng, Y., Gillette, T. G., Scherer, P. E., & Wang, Z. V. (2021) · Circulation · doi:10.1161/circulationaha.120.053125 · Cited by 116
Onukwufor, J. O., Berry, B. J., & Wojtovich, A. P. (2019) · Antioxidants · doi:10.3390/antiox8080285 · Cited by 117
“There are many small molecules called suppressors of complex I site I(Q) electron leak (S1QELs), that inhibit complex I at this site, preventing ROS production and protecting against IR injury [70,76,77].”
BackgroundJežek, P., Jabůrek, M., Holendová, B., Engstová, H., & Dlasková, A. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0173 · Cited by 117
“Is it at exactly the same locus at forward electron transfer and in conditions of RET?”
BackgroundInfluentialWang, Y., Zhao, R., Liu, D., Deng, W., Xu, G., Liu, W., Rong, J., Long, X., Ge, J., & Shi, B. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/4971261 · Cited by 108
“Oxidative stress originates mainly in the mitochondria from ROS and can be identified in the pathophysiology of the consequential clinical manifestations of cardiovascular diseases [48].”
Self-citationMitochondrial and cytosolic sources of hydrogen peroxide in resting C2C12 myoblasts
Wong, H. S., Benoit, B., & Brand, M. D. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.448 · Cited by 106
Self-citationWhy succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel
Murphy, M. P., & Chouchani, E. T. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01004-8 · Cited by 105
Acute O2 Sensing: Role of Coenzyme QH2/Q Ratio and Mitochondrial ROS Compartmentalization
Arias‐Mayenco, I., González‐Rodríguez, P., Torres‐Torrelo, H., Gao, L., Fernández-Agüera, M. C., Bonilla, V., Ortega‐Sáenz, P., & López‐Barneo, J. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.009 · Cited by 99
Mitochondria as Therapeutic Targets in Transplantation
Saeb‐Parsy, K., Martin, J. L., Summers, D. M., Watson, C. J. E., Krieg, T., & Murphy, M. P. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.08.001 · Cited by 88
“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].”
MethodTsuji, A., Akao, T., Masuya, T., Murai, M., & Miyoshi, H. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013366 · Cited by 84
Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer
Chen, D., Guo, Z., Yao, L., Sun, Y., Dian, Y., Zhao, D., Ke, Y., Zeng, F., Zhang, C., Deng, G., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103686 · Cited by 95
“Thus, complex I is recognized as the largest contributor to ROS production, although highly controversial [24,31 – 33], mainly because highly variable and difficult-to-measure factors influencing ROS production in vivo make it unachievable to evaluate ROS levels through isolated mitochondria [25].”
Small-Molecule Inhibitors of Reactive Oxygen Species Production
Sassetti, E., Clausen, M. H., & Laraia, L. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01914 · Cited by 85
Fock, E. M., & Parnova, R. G. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13020144 · Cited by 85
“S1QELs protected against ischemia-reperfusion injury in a perfused mouse heart [176].”
BackgroundBorkum, J. M. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03335-9 · Cited by 83
Wang, Y., Lilienfeldt, N., & Hekimi, S. (2024) · Physiological Reviews · doi:10.1152/physrev.00040.2023 · Cited by 88
Self-citationAutophagy promotes cell survival by maintaining NAD levels
Kataura, T., Sedlackova, L., Otten, E. G., Kumari, R., Shapira, D., Scialò, F., Stefanatos, R. K. A., Ishikawa, K., Kelly, G., Seranova, E., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.10.008 · Cited by 79
Treatment of the Fluoroquinolone‐Associated Disability: The Pathobiochemical Implications
Michalak, K. P., Sobolewska-Włodarczyk, A., Włodarczyk, M., Sobolewska, J., Woźniak, P., & Sobolewski, B. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/8023935 · Cited by 76
“[96], NADH2/NAD ratio (which can be called “hydrogen pressure”) is the main factor determining the escape of electrons from the ETC chain, making this process to high degree independent of the total ETC electron flow.”
BackgroundCoenzyme Q10: Novel Formulations and Medical Trends
Pastor‐Maldonado, C. J., Suarez-Rivero, J. M., Povea-Cabello, S., Álvarez-Córdoba, M., Villalón-García, I., Munuera-Cabeza, M., Suárez-Carrillo, A., Talaverón-Rey, M., & Sánchez-Alcázar, J. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228432 · Cited by 76
Gonçalves, R. L. S., Watson, M. A., Wong, H. S., Orr, A. L., & Brand, M. D. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101341 · Cited by 68
“S1QELs have proven useful for defining the contribution of site IQ under physio-pathological conditions in isolated mitochondria, in situ and in vivo [4,10,31,32].”
BackgroundInfluentialSelf-citationReactive Oxygen Species in intestinal stem cell metabolism, fate and function
Morris, O., & Jasper, H. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.015 · Cited by 70
Self-citationNDP52 acts as a redox sensor in PINK1/Parkin‐mediated mitophagy
Kataura, T., Otten, E. G., Rabanal‐Ruiz, Y., Adriaenssens, E., Urselli, F., Scialò, F., Fan, L., Smith, G. R., Dawson, W., Chen, X., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2022111372 · Cited by 69
“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 67
“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…”
BackgroundSelf-citationNADH/NAD+ Redox Imbalance and Diabetic Kidney Disease
Yan, L. (2021) · Biomolecules · doi:10.3390/biom11050730 · Cited by 69
Morris, O., Deng, H., Tam, C., & Jasper, H. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108423 · Cited by 59
“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
Rimal, S., Tantray, I., Li, Y., Khaket, T. P., Li, Y., Bhurtel, S., Li, W., Zeng, C., & Lu, B. (2023) · EMBO Reports · doi:10.15252/embr.202255548 · Cited by 60
Fukushima, C. T., Dancil, I.-S., Clary, H., Shah, N., Nadtochiy, S. M., & Brookes, P. S. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103047 · Cited by 68
“1(1 μ M) [18,19], or S3QEL-2 (3.3 μ M) [61], from 100x stocks in DMSO.”
BackgroundInfluentialSelf-citationReactive oxygen species control protein degradation at the mitochondrial import gate
McMinimy, R. A., Manford, A. G., Gee, C. L., Chandrasekhar, S., Mousa, G. A., Chuang, J., Phu, L., Shih, K. Y., Rose, C. M., Kuriyan, J., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.11.004 · Cited by 63
Jensen, M. B., Qi, Y., Riley, R. R., Rabkina, L., & Jasper, H. (2017) · eLife · doi:10.7554/elife.26952 · Cited by 63
“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
Plecitá‐Hlavatá, L., Engstová, H., Ježek, J., Holendová, B., Tauber, J. A., Petrásková, L., Křen, V., & Ježek, P. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/1826303 · Cited by 57
“, succinate accumulation, in cardiomyocytes during ischemia, while the concomitant superoxide burst is the primary damaging agent upon reperfusion in ischemic heart disease [45, 48].”
Marelja, Z., Leimkühler, S., & Missirlis, F. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00050 · Cited by 61
Mitochondrial dynamics, mitophagy and biogenesis in neonatal hypoxic‐ischaemic brain injury
Thornton, C., Jones, A., Nair, S., Aabdien, A., Mallard, C. E., & Hagberg, H. (2017) · FEBS Letters · doi:10.1002/1873-3468.12943 · Cited by 58
Cobley, J. N. (2020) · Antioxidants · doi:10.3390/antiox9100933 · Cited by 57
Metabolic determinants of cellular fitness dependent on mitochondrial reactive oxygen species
Kong, H., Reczek, C. R., McElroy, G. S., Steinert, E. M., Wang, T., Sabatini, D. M., & Chandel, N. S. (2020) · Science Advances · doi:10.1126/sciadv.abb7272 · Cited by 56
“3B) ( 26 ).”
Current perspectives of mitochondria-targeted antioxidants in cancer prevention and treatment
Zinovkin, R. A., Lyamzaev, K. G., & Chernyak, B. V. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1048177 · Cited by 56
“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).”
BackgroundForte, M., Palmerio, S., Bianchi, F., Volpe, M., & Rubattu, S. D. (2019) · Journal of Molecular Medicine · doi:10.1007/s00109-019-01771-3 · Cited by 50
Cork-in-bottle mechanism of inhibitor binding to mammalian complex I
Chung, I., Serreli, R., Cross, J. B., Francesco, M. E. D., Marszalek, J. R., & Hirst, J. (2021) · Science Advances · doi:10.1126/sciadv.abg4000 · Cited by 50
Perspectives on mitochondrial relevance in cardiac ischemia/reperfusion injury
Pedriali, G., Ramaccini, D., Bouhamida, E., Wieckowski, M. R., Giorgi, C., Tremoli, E., & Pinton, P. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1082095 · Cited by 55
Pathophysiology of reactive oxygen species (ROS)
de la Lastra, J. M. P., Andrés, C. M. C., Munguira, E. B., Juan, C. A., & Pérez‐Lebeña, E. (2026) · Archives of Toxicology · doi:10.1007/s00204-025-04276-w · Cited by 61
“…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
Détaille, D., Pasdois, P., Sémont, A., Santos, P. D. D., & Diolez, P. (2019) · PLoS ONE · doi:10.1371/journal.pone.0216385 · Cited by 53
“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].”
BackgroundMethodInfluentialHomma, T., Kobayashi, S., Sato, H., & Fujii, J. (2021) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2021.108775 · Cited by 51
Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis
Chen, Z., Ho, I.-L., Soeung, M., Yen, E.-Y., Liu, J., Liang, Y., Rose, J. L., Srinivasan, S., Jiang, S., Chang, Q., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37924-9 · Cited by 52
Fiorenza, M., Onslev, J., Henríquez‐Olguín, C., Persson, K. W., Hesselager, S. A., Jensen, T. E., Wojtaszewski, J. F. P., Hostrup, M., & Bangsbo, J. (2024) · Science Advances · doi:10.1126/sciadv.adq4461 · Cited by 58
Coenzyme Q redox signalling and longevity
Scialò, F., & Sanz, A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.018 · Cited by 48
The role of mitochondrial reactive oxygen species in insulin resistance
Ayer, A., Fazakerley, D. J., James, D. E., & Stocker, R. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.11.007 · Cited by 50
Wong, H. S., Monternier, P., & Brand, M. D. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.09.006 · Cited by 46
Self-citationNAD Depletion Mediates Cytotoxicity in Human Neurons With Autophagy Deficiency
Sun, C., Seranova, E., Cohen, M. A., Chipara, M., Roberts, J., Astuti, D., Palhegyi, A. M., Acharjee, A., Sedlackova, L., Kataura, T., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2023.112372 · Cited by 43
Association between ROS production, swelling and the respirasome integrity in cardiac mitochondria
Jang, S., & Javadov, S. A. (2017) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2017.07.009 · Cited by 45
Li, Q., Yu, Z., Xiao, D., Wang, Y., Zhao, L., An, Y., & Gao, Y. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14903 · Cited by 43
Self-citationHatinguais, R., Pradhan, A., Brown, G. D., Brown, A. J. P., Warris, A., & Shekhova, E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.641495 · Cited by 41
“1, an antioxidant that suppresses mitoROS via RET (43), decreased TNF-a and IL-1b production by BMDMs exposed to swollen conidia.”
BackgroundHeart specific knockout of Ndufs4 ameliorates ischemia reperfusion injury
Zhang, H., Gong, G., Wang, P., Zhang, Z., Kolwicz, S. C., Rabinovitch, P. S., Tian, R., & Wang, W. (2018) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2018.08.022 · Cited by 39
“Indeed, previous reports have shown that either blocking forward or reverse electron flow protected against I/R injury [12, 38].”
BackgroundIncreased glycolysis is an early consequence of palmitate lipotoxicity mediated by redox signaling
Kakimoto, P. A., Serna, J. D. C., Ramos, V. D. M., Antonio Zorzano, A., & Kowaltowski, A. J. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102026 · Cited by 41
Barnig, C., Lutzweiler, G., Giannini, M., Lejay, A., Charles, A., Meyer, A., & Gény, B. (2022) · Antioxidants · doi:10.3390/antiox11061213 · Cited by 44
Zhang, Y., Zhang, Y., Xiao, Z., Zhang, Y., Zhang, J., Li, Z., & Zhu, Y. (2018) · Journal of Molecular Medicine · doi:10.1007/s00109-018-1649-2 · Cited by 40
“Therefore, there is a possibility that complex I may be involved for CFTR defect-mediated mitochondrial oxidative stress [49, 50].”
BackgroundMeng, K., Jiao, J., Zhu, R., Wang, B.-Y., Mao, X., Zhong, Y., Zhu, Z., Yu, K., Ding, Y. P., Xu, W., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/1645249 · Cited by 40
“Superoxide-H2O2 have been identified as the key component of ROS and contributed to the development of I/R-induced cardiac dysfunction [43, 44].”
BackgroundTargeted Antioxidants in Exercise-Induced Mitochondrial Oxidative Stress: Emphasis on DNA Damage
Williamson, J., & Davison, G. W. (2020) · Antioxidants · doi:10.3390/antiox9111142 · Cited by 43
Sávio-Silva, C., Soinski-Sousa, P. E., Simplício-Filho, A., Bastos, R. M. C., Beyerstedt, S., & Rangel, É. B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041546 · Cited by 42
“Accumulated O2-H2O2 causes mitochondrial disturbance through redox balance alterations in ETC, culminating in energy failure and inducing cell death [24].”
BackgroundMilliken, A. S., Nadtochiy, S. M., & Brookes, P. S. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.122.026135 · Cited by 41
Self-citationOxidation of retromer complex controls mitochondrial translation
Zhang, J., Ali, M. Y., Chong, H. B., Tien, P.-C., Woods, J., Noble, C., Vornbäumen, T., Ordulu, Z., Possemato, A. P., Harry, S., et al. (2025) · Nature · doi:10.1038/s41586-025-08756-y · Cited by 38
Banba, A., Tsuji, A., Kimura, H., Murai, M., & Miyoshi, H. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007687 · Cited by 40
“5 maintained its inhibitory effects in the previous high-throughput screening with isolated mitochondria (24).”
BackgroundMethodInfluentialPlecitá‐Hlavatá, L., Engstová, H., Holendová, B., Tauber, J. A., Špaček, T., Petrásková, L., Křen, V., Špačková, J., Gotvaldová, K., Ježek, J., et al. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7800 · Cited by 37
“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
Wright, J. J., Biner, O., Chung, I., Burger, N., Bridges, H. R., & Hirst, J. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c00274 · Cited by 37
Barnett, D., Zimmer, T. S., Booraem, C., Palaguachi, F., Meadows, S. M., Xiao, H., Wong, M. Y., Luo, W., Gan, L., Chouchani, E. T., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01390-y · Cited by 41
“As reported in other cell types 3,4,6,29 , S3QELs and S1QELs did not affect mitochondrial metabolism (Extended Data Fig.”
InfluentialSelf-citation
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
