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

Area of Science:

• Mitochondrial biology
• Epigenetics
• Cellular metabolism

Background:

• Mitochondrial inner membrane potential (ΔΨm) maintenance is crucial for cellular function.
• While ΔΨm loss is studied, the effects of mitochondrial hyperpolarization remain largely unknown.
• ATP5IF1 (IF1) inhibits ATP synthase's hydrolytic activity, and its deletion causes increased resting ΔΨm.

Purpose of the Study:

• To investigate the effects of chronic mitochondrial hyperpolarization on cellular epigenetics and gene expression.
• To identify the molecular mechanisms linking mitochondrial membrane potential to the epigenome.
• To explore the role of mitochondrial hyperpolarization in cellular adaptation and disease.

Main Methods:

• Utilized ATP5IF1-deleted cells as a model for increased resting ΔΨm.
• Investigated nuclear DNA methylation and gene transcription in hyperpolarized cells.
• Examined phospholipid, redox, and metabolic changes in response to altered ΔΨm.
• Recapitulated effects in wild-type cells exposed to hyperpolarizing chemicals.
• Analyzed ovarian cancer cells with naturally depleted IF1.

Main Results:

• Chronic mitochondrial hyperpolarization leads to nuclear DNA hypermethylation.
• Hypermethylation regulates the transcription of mitochondrial, carbohydrate, and lipid genes.
• Phospholipid alterations, not redox or metabolic changes, mediate the link between ΔΨm and the epigenome.
• These effects are reversible by decreasing ΔΨm and observed in ovarian cancer cells.

Conclusions:

• Mitochondrial hyperpolarization induces epigenetic modifications via DNA hypermethylation.
• Phospholipid remodeling is a key adaptation to sustained high ΔΨm.
• Mitochondria can influence epigenetics, impacting cellular biology, health, chemical exposures, and disease states.