Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling

Mateus Prates Mori, Oswaldo A. Lozoya, Ashley M. Brooks, Carl D. Bortner, Cristina A. Nadalutti, Birgitta Ryback, Brittany P. Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky and Janine H. Santos ()
Additional contact information
Mateus Prates Mori: National Institutes of Health (NIH)
Oswaldo A. Lozoya: National Institutes of Health (NIH)
Ashley M. Brooks: National Institutes of Health (NIH)
Carl D. Bortner: National Institutes of Health (NIH)
Cristina A. Nadalutti: National Institutes of Health (NIH)
Birgitta Ryback: Harvard Medical School
Brittany P. Rickard: University of North Carolina (UNC)
Marta Overchuk: North Carolina State University
Imran Rizvi: North Carolina State University
Tatiana Rogasevskaia: Mount Royal University
Kai Ting Huang: Thomas Jefferson University
Prottoy Hasan: Thomas Jefferson University
György Hajnóczky: Thomas Jefferson University
Janine H. Santos: National Institutes of Health (NIH)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-59427-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59427-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-59427-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().