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

Author

Listed:
  • 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
    UNC)

  • 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))

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.

Suggested Citation

  • 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 , 2025. "Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59427-5
    DOI: 10.1038/s41467-025-59427-5
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    References listed on IDEAS

    as
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