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bioRxiv · 10.1101/2024.01.12.575075

Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling

Mori, M. P.·Lozoya, O.·Brooks, A.·Grenet, D.·Nadalutti, C.·Ryback, B.·Huang, K.-T.·Hasan, P.·Hajnoczky, G.·Santos, J.
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Abstract

Maintenance of the mitochondrial inner membrane potential ({Delta}{Psi}M) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While {Delta}{Psi}M loss and its consequences are well studied, little is known about the effects of increased {Delta}{Psi}M. In this study, we used cells deleted of ATPIF1, a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of mitochondrial hyperpolarization. Our data show that chronic {Delta}{Psi}M increase leads to nuclear DNA hypermethylation, regulating transcription of mitochondria, carbohydrate and lipid metabolism genes. Surprisingly, remodeling of phospholipids, but not metabolites or redox changes, mechanistically links the {Delta}{Psi}M to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the {Delta}{Psi}M, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the {Delta}{Psi}M as the upstream signal conveying the mitochondrial status to the epigenome to regulate cellular biology, providing a new framework for how mitochondria can influence health outcomes in the absence of canonical dysfunction. HighlightsO_LIMitochondria hyperpolarization leads to nuclear DNA hypermethylation C_LIO_LIDNA methylation regulates expression of mitochondrial and lipid metabolism genes C_LIO_LIPhospholipid remodeling mediates the epigenetic effects of mitochondrial hyperpolarization C_LI

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Mori, M. P., Lozoya, O., Brooks, A., Grenet, D., Nadalutti, C., Ryback, B., Huang, K.-T., Hasan, P., Hajnoczky, G., Santos, J.. 2024-01-13. Mitochondrial membrane potential regulates nuclear DNA methylation and gene expression through phospholipid remodeling. https://doi.org/10.1101/2024.01.12.575075

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