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Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy [RNA-seq]

ABSTRACT: Metabolic dysfunction associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This lipotoxicity in the liver is associated with dysregulation of the first step in lipid catabolism called beta oxidation in the mitochondrial matrix, eventually leading to mitochondrial dysfunction. To evaluate possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and to a lesser extent CpG methylation increase bile acid metabolic gene expression, inducing cholestasis by mito-nuclear epigenetic reprogramming. Moreover, increased expression of metabolic nuclear receptors in both MSssI and MCviPI cells promote mitochondrial swelling and induce basal overactivation of mitochondrial respiration which favours lipid accumulation and metabolic-stress induced mitophagy and autophagy stress responses. Altogether GpC and CpG mitochondrial induce a metabolic challenging environment that is similar to mitochondrial dysfunction in the progression of MASLD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241526 | GEO | 2023/12/08

REPOSITORIES: GEO

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Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy

Project description:Metabolic dysfunction associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This lipotoxicity in the liver is associated with dysregulation of the first step in lipid catabolism called beta oxidation in the mitochondrial matrix, eventually leading to mitochondrial dysfunction. To evaluate possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and to a lesser extent CpG methylation increase bile acid metabolic gene expression, inducing cholestasis by mito-nuclear epigenetic reprogramming. Moreover, increased expression of metabolic nuclear receptors in both MSssI and MCviPI cells promote mitochondrial swelling and induce basal overactivation of mitochondrial respiration which favours lipid accumulation and metabolic-stress induced mitophagy and autophagy stress responses. Altogether GpC and CpG mitochondrial induce a metabolic challenging environment that is similar to mitochondrial dysfunction in the progression of MASLD.

2023-12-08 | GSE240988 | GEO

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) [MouseMethylation]

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Project description:Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy

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Project description:Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20‑30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver‑specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied transcriptome profile changes that could induce changes in DNA methylation in liver biopsies of WT and hepatocyte‑specific PPARα KO mice, following a 6‑week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte‑specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet‑induced loss of PPARα function triggers compensatory transcription of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis‑pyroptosis lipid damage associated pathways towards MASLD fibrosis.

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Induction ofsteatosis in primary human hepatocytes manifests into hepatic pathophysiology of metabolic dysfunction-associated liver disease

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Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy [RNA-seq]

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