Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling
Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.
Authors
- Brittany P. Rickard (ORCID: https://orcid.org/0000-0002-6112-1290)
- Janine H. Santos (ORCID: https://orcid.org/0000-0001-6384-3070)
- Imran Rizvi (ORCID: https://orcid.org/0000-0001-9673-4700)
- Cristina A. Nadalutti (ORCID: https://orcid.org/0000-0002-4721-6904)
- Ashley Brooks (ORCID: https://orcid.org/0000-0002-9189-1114)
- Oswaldo A. Lozoya (ORCID: https://orcid.org/0000-0001-6779-7382)
- Carl D. Bortner (ORCID: https://orcid.org/0000-0002-5444-6628)
- György Hajnóczky (ORCID: https://orcid.org/0000-0003-3813-2570)
- Prottoy Hasan (ORCID: https://orcid.org/0000-0001-9968-3400)
- Marta Overchuk (ORCID: https://orcid.org/0000-0002-8203-0427)
- Birgitta Ryback (ORCID: https://orcid.org/0009-0006-7773-6878)
- Tatiana P. Rogasevskaia (ORCID: https://orcid.org/0000-0002-1335-8365)
- Mateus Prates Mori (ORCID: https://orcid.org/0000-0003-1349-6378)
- Kai Ting Huang
Institutions
- University of North Carolina at Chapel Hill (US)
- National Institutes of Health (US)
- University of North Carolina Health Care (US)
- Harvard University (US)
- North Carolina State University (US)
- Thomas Jefferson University (US)
- National Institute of Environmental Health Sciences (US)
- Dana-Farber Cancer Institute (US)
- UNC Lineberger Comprehensive Cancer Center
- Mount Royal University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1038/s41467-025-59427-5
- Citations
- 11
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 8.87
Funders
- Thomas Jefferson University
- Center for Strategic Scientific Initiatives, National Cancer Institute
- Mount Royal University
- National Institutes of Health
- National Institute of Environmental Health Sciences