Search

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. [Display omitted] • Crucial roles of Drp1 in TGF-β1 induced HSC proliferation and migration and mitochondrial fission. • ALKBH5 mediated m6A demethylation in the 3'UTR of Drp1 mRNA and induced its translation. • ALKBH5 loss upregulated Drp1 levels in an m6A-YTHDF1-dependent manner. [ABSTRACT FROM AUTHOR]

Abstract: We have generated a quantitative transcription profile of human bocavirus type 1 (HBoV1) by transfecting a nearly full-length clone in human lung epithelial A549 cells as well as in a replication competent system in 293 cells. The overall transcription profile of HBoV1 is similar to that of two other members of genus Bocavirus, minute virus of canines and bovine parvovirus 1. In particular, a spliced NS1-transcript that was not recognized previously expressed the large non-structural protein NS1 at approximately 100kDa; and the NP1-encoding transcripts were expressed abundantly. In addition, the protein expression profile of human bocavirus type 2 (HBoV2) was examined in parallel by transfection of a nearly full-length clone in A549 cells, which is similar to that of HBoV1. Moreover, our results showed that, unlike human parvovirus B19 infection, expression of the HBoV1 proteins only does not induce cell cycle arrest and apoptosis of A549 cells. [Copyright &y& Elsevier]