The role of the apoptosis-related protein BCL-B in the regulation of mitophagy in hepatic stellate cells during the regression of liver fibrosis

The clearance of activated hepatic stellate cells (HSCs) by apoptosis is critical for the reversibility of hepatic fibrosis. Mitochondrial homeostasis is regulated by mitophagy, which is an efficient way of clearing injured mitochondria that plays an important role in apoptosis. However, the role of mitophagy in apoptosis in HSCs and hepatic fibrosis is still unclear. Here, we show that mitophagy is enhanced in parallel with increased apoptosis in hepatic stellate cells during the reversal of hepatic fibrosis. The inhibition of mitophagy suppressed apoptosis in HSCs and aggravated hepatic fibrosis in mice. In contrast, the activation of mitophagy induced apoptosis in HSCs. Furthermore, we confirmed that BCL-B, which is a member of the BCL-2 family, is a regulator mediating mitophagy-related apoptosis. The knockdown of BCL-B resulted in increased apoptosis and mitophagy in HSCs, while the overexpression of BCL-B caused the opposite effects. BCL-B inhibited the phosphorylation of Parkin (a key regulator of mitophagy) and directly bound phospho-Parkin. Altogether, enhanced mitophagy promotes apoptosis in HSCs during the reversal of hepatic fibrosis. BCL-B suppresses mitophagy in HSCs by binding and suppressing phospho-Parkin, thereby inhibiting apoptosis. BCL-B-dependent mitophagy is a new pathway for the regulation of apoptosis in HSCs during the regression of hepatic fibrosis. Liver fibrosis: cleaning up injured mitochondria helps reverse tissue scarring Clearing away defective mitochondria helps destroy cells in the liver that contribute to tissue scarring; the signaling pathway involved offers a new therapeutic target. Hui-Qing Jiang and colleagues from the Hebei Institute of Gastroenterology in Shijiazhuang, China, induced liver fibrosis in mice and showed that as the animals recovered and the damage to their liver tissue was reversed, injured mitochondria were cleared from fibrosis-causing cells in tandem with the cells’ controlled destruction. Experimentally inhibiting the process of mitochondrial clearance also inhibited cell death and aggravated fibrotic scarring in the mice. The researchers identified a signaling pathway that regulates mitochondrial cleanup and, in turn, also controlled cell death. Targeting this pathway offer a potential new therapeutic strategy for reversing liver fibrosis in patients.