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bioRxiv · 10.1101/2025.05.29.656565

Complex I inhibition shifts mitochondrial dynamics and regulates cancer cell survival, providing a synthetic lethal interaction

Bhati, F. K.·Saha, U.·Singh, S.·Bhat, M. K.
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Abstract

Mitochondrial remodeling has emerged as a key regulator of cancer cell metabolism, cell stemness, development of drug resistance, and induction of apoptosis. Metformin, a clinically approved inhibitor of mitochondrial complex I, has shown variable antitumor activity in preclinical and clinical settings, implying that adaptive mitochondrial responses can buffer its cytotoxic effects. Here, we show that metformin reprograms mitochondrial dynamics in liver and colorectal cancer cells, increases mitochondrial biomass, alters fusion-fission balance, and enhances biogenesis in a cell type-dependent manner. These adaptations preserve mitochondrial function and support survival under metformin-induced energetic stress. Notably, the targeted disruption of these mitochondrial adaptations induces cell death in metformin-treated cancer cells and suppresses tumor growth. Overall, the study identifies metformin-driven mitochondrial remodeling as a central adaptive axis to complex I inhibition and provides a rationale for co-targeting mitochondrial dynamics and metabolism to enhance the anticancer efficacy of metformin.

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Bhati, F. K., Saha, U., Singh, S., Bhat, M. K.. 2025-06-01. Complex I inhibition shifts mitochondrial dynamics and regulates cancer cell survival, providing a synthetic lethal interaction. https://doi.org/10.1101/2025.05.29.656565

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