Epigenetic control of mitochondrial fission enables hepatic stellate cells activation in liver fibrosis via PGC-1α-Drp1 pathway

Abstract

Although excessive mitochondrial fission is linked to cell activation, its significance in hepatic stellate cells (HSCs) activation and liver fibrosis is unknown. Here we show that excessive mitochondrial fission triggers HSCs activation and liver fibrosis degradation by the epigenetic regulation. We used a combination of in vitro and in vivo models including HSCs, clinical cases, and CCl₄-induced liver fibrosis mice to investigate the regulation and function of mitochondrial fission in HSCs activation and liver fibrosis. Herein, we show that DNMT3A and Drp1 is up regulated in fibrosis livers and mice liver fibrosis tissues, while PGC-1α was decreased. Interestingly, down expression of DNMT3A substantially reduced Drp1 levels, collagen accumulation, and interstitial fibrosis, while significantly increased PGC-1α levels. Furthermore, silencing DNMT3A remarkably inhibits HSCs activation and mitochondrial fission both in vivo and in vitro. Mechanistically, co-immunoprecipitation analysis revealed that DNMT3A bound to pull down the protein of PGC-1α. These findings indicated that epigenetic control of mitochondrial fission enables HSCs activation in liver fibrosis via PGC-1α-Drp1 pathway, and provide new insight into the relationship between mitochondrial fission and liver fibrosis.

Keywords: Activation; DNMT3A; Drp1; Hepatic stellate cells; Liver fibrosis; Mitochondrial fission.