ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation

Pharmacol Res. 2023 Jan:187:106608. doi: 10.1016/j.phrs.2022.106608. Epub 2022 Dec 21.

Abstract

Mitochondrial metabolism plays a pivotal role in various cellular processes and fibrosis. However, the mechanism underlying mitochondrial metabolic function and liver fibrosis remains poorly understood. In this study, we determined whether mitochondrial metabolism mediates liver fibrosis using cells, animal models, and clinical samples to elucidate the potential effects and underlying mechanism of mitochondrial metabolism in liver fibrosis. We report that AlkB Homolog 5 (ALKBH5) decreases mitochondrial membrane potential (MMP) and oxygen consumption rate (OCR), suppresses mitochondrial fission and hepatic stellate cell (HSC) proliferation and migration and ameliorates liver fibrosis. Enhancement of mitochondrial fission, an essential event during HSC proliferation and migration, is dependent on decreased ALKBH5 expression. Furthermore, we reveal that low ALKBH5 expression is associated with elevated N6-methyladenosine (m6A) mRNA levels. Mechanistically, ALKBH5 mediates m6A demethylation in the 3'UTR of Drp1 mRNA and induces its translation in a YTH domain family proteins 1 (YTHDF1)-independent manner. Subsequently, in transforming growth factor-β1 (TGF-β1) induced HSC, Dynamin-related protein 1 (Drp1) mediates mitochondrial fission and increases cell proliferation and migration. Decreased Drp1 expression inhibits mitochondrial fission and suppresses HSC proliferation and migration. Notably, human fibrotic liver and heart tissue exhibited enhanced mitochondrial fission; increased YTHDF1, Drp1, alpha-smooth muscle actin (α-SMA) and collagen I expression; decreased ALKBH5 expression and increased liver fibrosis. Our results highlight a novel mechanism by which ALKBH5 suppresses mitochondrial fission and HSC proliferation and migration by reducing Drp1 methylation in an m6A-YTHDF1-dependent manner, which may indicate a demethylation-based approach for liver fibrosis diagnosis and therapy.

Keywords: ALKBH5; Drp1; Hepatic stellate cells; Liver fibrosis; Mitochondrial fission; YTHDF1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AlkB Homolog 5, RNA Demethylase / genetics
  • AlkB Homolog 5, RNA Demethylase / metabolism
  • Animals
  • Dynamins / metabolism
  • Hepatic Stellate Cells
  • Humans
  • Liver Cirrhosis* / metabolism
  • Methylation
  • Mitochondrial Dynamics*
  • RNA, Messenger / metabolism

Substances

  • Dynamins
  • RNA, Messenger
  • ALKBH5 protein, human
  • AlkB Homolog 5, RNA Demethylase