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Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [EPIC1]

ABSTRACT: Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [EPIC1]

PROVIDER: PRJNA1254147 | ENA |

REPOSITORIES: ENA

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Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [EPIC1]

Project description: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.

2025-04-22 | GSE295300 | GEO

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [EPICv2]

2025-04-22 | GSE295015 | GEO

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [RNA-Seq]

2025-04-22 | GSE295296 | GEO

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [EPICv2]

Project description:Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [EPICv2]

| PRJNA1252461 | ENA

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [RNA-Seq]

Project description:Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling [RNA-Seq]

| PRJNA1254136 | ENA

Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis.

Project description:Background and aims: NASH, characterized by inflammation and fibrosis, is emerging as a leading etiology of HCC. Lipidomics analyses in the liver have shown that the levels of polyunsaturated phosphatidylcholine (PC) are decreased in patients with NASH, but the roles of membrane PC composition in the pathogenesis of NASH have not been investigated. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a phospholipid (PL) remodeling enzyme that produces polyunsaturated PLs, is a major determinant of membrane PC content in the liver. Approach and results: The expression of LPCAT3 and the correlation between its expression and NASH severity were analyzed in human patient samples. We examined the effect of Lpcat3 deficiency on NASH progression using Lpcat3 liver-specific knockout (LKO) mice. RNA sequencing, lipidomics, and metabolomics were performed in liver samples. Primary hepatocytes and hepatic cell lines were used for in vitro analyses. We showed that LPCAT3 was dramatically suppressed in human NASH livers, and its expression was inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency enhances reactive oxygen species production due to impaired mitochondrial homeostasis. Loss of Lpcat3 increases inner mitochondrial membrane PL saturation and elevates stress-induced autophagy, resulting in reduced mitochondrial content and increased fragmentation. Furthermore, overexpression of Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH. Conclusions: These results demonstrate that membrane PL composition modulates the progression of NASH and that manipulating LPCAT3 expression could be an effective therapeutic for NASH.

2024-06-05 | GSE218075 | GEO

Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis.

Project description:Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis.

| PRJNA902270 | ENA

Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis [Lpcat3_OE]

Project description:Nonalcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis, is emerging as a leading etiology of hepatocellular carcinoma (HCC). However, the mechanisms underlying the pathogenesis of NASH are not well understood. Here, we show that membrane phospholipid (PL) composition determined by a remodeling process modulates the progression of NASH. The expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), a PL remodeling enzyme that produces polyunsaturated PLs, is dramatically suppressed in human NASH livers compared to controls. LPCAT3 expression is inversely correlated with NAFLD activity score and fibrosis stage. Loss of Lpcat3 in mouse liver promotes the development of both spontaneous and diet-induced NASH/HCC. Mechanistically, Lpcat3 deficiency increases reactive oxygen species production, likely due to impaired mitochondrial homeostasis as demonstrated by reduced mitochondrial DNA content and fragmented mitochondrial morphology. Overexpressing Lpcat3 in the liver ameliorates inflammation and fibrosis of NASH. These results suggest that manipulating LPCAT3 expression may be an effective therapeutic strategy for NASH.

2024-06-05 | GSE218074 | GEO

Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis [LKO_NASH]

2024-06-05 | GSE218073 | GEO

Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis [LKO_NASH]

Project description:Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis [LKO_NASH]

| PRJNA902276 | ENA

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