Mitochondrial Lipid Peroxidation Initiates Rapid Accumulation of Lipofuscin in Cultured Cells

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He Huan¹, Alisa A. Panteleeva¹, Ruben A. Simonyan¹, Armine V. Avetisyan¹, Konstantin G. Lyamzaev^1,2,a*, and Boris V. Chernyak¹

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

²Russian Clinical Research Center of Gerontology, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, 129226 Moscow, Russia

^* To whom correspondence should be addressed.

Received: August 15, 2025; Revised: September 12, 2025; Accepted: September 16, 2025

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Activation of lipid peroxidation (LPO) in the mitochondria of rat H9c2 cardiomyoblasts and human fibroblasts by the cystine transport inhibitor erastin or glutathione peroxidase 4 inhibitor RSL3 was accompanied by rapid (18 h) accumulation of lipofuscin. The mitochondria-targeted antioxidant SkQ1 and redox mediator methylene blue, which prevents the formation of reactive oxygen species (ROS) in the mitochondrial respiratory chain complex I, blocked both mitochondrial LPO and lipofuscin accumulation. These data indicate that mitochondrial LPO serves as a driving force for the accelerated accumulation of lipofuscin in cells. Rapid (24 h) lipofuscin formation was observed in isolated heart mitochondria in the presence of iron ions. It was significantly accelerated by ROS generated in the respiratory chain complex I and blocked by SkQ1. The question of whether oxidized components of mitochondria serve as a source for lipofuscin formation in cells remains open. The results obtained suggest possible application of mitochondria-targeted compounds in the treatment of diseases associated with excessive lipofuscin accumulation.

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KEY WORDS: lipid peroxidation, mitochondria, ferroptosis, lipofuscin

DOI: 10.1134/S0006297925602606

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