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

Abstract

Maintenance of the mitochondrial inner membrane potential (MMP) is critical for many aspects of mitochondrial function, including mitochondrial protein import and ion homeostasis. While MMP loss and its consequences are well studied, little is known about the effects of increased MMP. 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 MMP 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 MMP to the epigenome. These changes were also observed upon chemical exposures and reversed by decreasing the MMP, highlighting them as hallmark adaptations to chronic mitochondrial hyperpolarization. Our results reveal the MMP 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.