REVIEW: Suppressing Mitochondrial ROS Production is Beneficial in Multiple Preclinical Models of Human Disease

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Martin D. Brand^1,a*

¹Buck Institute for Research on Aging, Novato, California 94945, USA

^* To whom correspondence should be addressed.

Received: August 12, 2025; Revised: September 24, 2025; Accepted: September 29, 2025

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I discuss the therapeutic potential of site-specific suppressors of the production of mitochondrial reactive oxygen species (ROS). The best-defined suppressors are S1QELs (targeting site I_Q in complex I) and S3QELs (targeting site III_Qo in complex III). They prevent ROS formation at source without affecting oxidative phosphorylation. The antidiabetic drug imeglimin and the anti-xerostomia and antischistosomal anethole dithiolethiones also have S1QEL activity, although how much this contributes to their clinical effects needs further study. Suppressing mitochondrial ROS production has therapeutic potential in many diseases. S1QELs and imeglimin improve glucose tolerance, insulin sensitivity, and decrease hepatic steatosis in models of diabetes and obesity. S1QELs and S3QELs protect against age-related cardiac decline, atrial fibrillation and hypertension. They reduce inflammatory cytokines and oxidative stress in macrophages and other cells. They inhibit cancer cell proliferation and tumour growth. In neurological diseases, S1QELs protect against noise-induced hearing loss. S1QELs protect against cardiac and hepatic damage during ischemia-reperfusion. S1QELs and S3QELs extend lifespan in model organisms and S3QELs protect against aging-related intestinal barrier dysfunction. Suppressors mitigate drug-induced toxicities (e.g., acetaminophen, cisplatin) and the effects of environmental stressors. In exocrinopathy, anethole dithiolethione alleviates symptoms of dry mouth and dry eye. Suppressors of mitochondrial ROS production show promise in treating a wide range of diseases driven by mitochondrial oxidative stress. Their mechanism-based specificity offers advantages over traditional antioxidants, with potential applications in metabolic, cardiovascular, inflammatory, neurological, and aging-related diseases. Further research is needed to fully explore their clinical efficacy.

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KEY WORDS: mitochondria, ROS, S1QEL, S3QEL, imeglimin, anethole dithiolethione, type 2 diabetes, cardiomyopathy, inflammation, cancer, noise-induced hearing loss, ischemia/reperfusion injury, aging, acetaminophen, cisplatin

DOI: 10.1134/S0006297925602527

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