Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59427-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850042619123466240 |
|---|---|
| author | 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 Janine H. Santos |
| author_facet | 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 Janine H. Santos |
| author_sort | Mateus Prates Mori |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-928c4c44ab524ebcbccb9c1103be9e7b |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-928c4c44ab524ebcbccb9c1103be9e7b2025-08-20T02:55:29ZengNature PortfolioNature Communications2041-17232025-04-0116112010.1038/s41467-025-59427-5Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodelingMateus Prates Mori0Oswaldo A. Lozoya1Ashley M. Brooks2Carl D. Bortner3Cristina A. Nadalutti4Birgitta Ryback5Brittany P. Rickard6Marta Overchuk7Imran Rizvi8Tatiana Rogasevskaia9Kai Ting Huang10Prottoy Hasan11György Hajnóczky12Janine H. Santos13Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Biostatistics and Computational Biology Branch, Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Flow Cytometry Center, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH)Dana Farber Cancer Institute, Harvard Medical SchoolCurriculum in Toxicology & Environmental Medicine, University of North Carolina (UNC)Department of Biomedical Engineering, North Carolina State UniversityDepartment of Biomedical Engineering, North Carolina State UniversityDepartment of Biology, Mount Royal UniversityMitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson UniversityMitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson UniversityMitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson UniversityMechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences (NIEHS), 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.https://doi.org/10.1038/s41467-025-59427-5 |
| spellingShingle | 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 Janine H. Santos Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling Nature Communications |
| title | Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling |
| title_full | Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling |
| title_fullStr | Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling |
| title_full_unstemmed | Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling |
| title_short | Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling |
| title_sort | mitochondrial membrane hyperpolarization modulates nuclear dna methylation and gene expression through phospholipid remodeling |
| url | https://doi.org/10.1038/s41467-025-59427-5 |
| work_keys_str_mv | AT mateuspratesmori mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT oswaldoalozoya mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT ashleymbrooks mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT carldbortner mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT cristinaanadalutti mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT birgittaryback mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT brittanyprickard mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT martaoverchuk mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT imranrizvi mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT tatianarogasevskaia mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT kaitinghuang mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT prottoyhasan mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT gyorgyhajnoczky mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling AT janinehsantos mitochondrialmembranehyperpolarizationmodulatesnucleardnamethylationandgeneexpressionthroughphospholipidremodeling |