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

Abstract

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.

Role of Mitofusins and Mitophagy in Life or Death Decisions

“…A pro-apoptotic mechanism of mitophagy was also reported. Induction of mitophagy in cancer cells, by treatment with valinomycin, Abrus agglutinin (AGG), abiraterone or MDV3100 (anti-cancer drugs), led to an increase in apoptosis, facilitating cancer recovery (Panda et al, 2018;Ding et al, 2019;Han et al, 2019). The Bcl-2 family member BCL-B and the levels of phosphorylated Parkin appeared to be central in this response (Ding et al, 2019).…”

“…Induction of mitophagy in cancer cells, by treatment with valinomycin, Abrus agglutinin (AGG), abiraterone or MDV3100 (anti-cancer drugs), led to an increase in apoptosis, facilitating cancer recovery ( Panda et al, 2018 ; Ding et al, 2019 ; Han et al, 2019 ). The Bcl-2 family member BCL-B and the levels of phosphorylated Parkin appeared to be central in this response ( Ding et al, 2019 ). Consistently, Parkin silencing decreased the death rate of hepatocellular carcinoma cells ( Prieto-Domínguez et al, 2016 ).…”

“…Thus, elimination of dysfunctional mitochondria by mitophagy is critical for cellular survival (Pickles et al, 2018;Allen and Baehrecke, 2020;Markaki and Tavernarakis, 2020). Despite being mostly pro-survival, mitophagy can also synergize with apoptosis to instead promote cell death (Yee et al, 2010;Panda et al, 2018;Ding et al, 2019;Han et al, 2019). Here, we discuss how the mitochondrial fusion factors, mitofusins, impact on mitophagy and apoptosis, present pro-survival and pro-apoptotic roles of mitophagy and detail the roles of mitophagy and mitofusin 2 in non-alcoholic fatty liver disease (NAFLD).…”

Mitochondrial dysfunction in fibrotic diseases

“…BCL-B belongs to the BCL-2 protein family, inhibits autophagy by binding Parkin signal and inhibiting its phosphorylation. BCL-B knockdown activates mitophagy, promotes apoptosis of HSCs and prevents fibrosis 124 . However, self-renewal mediated by mitophagy is not always beneficial to alleviating fibrosis.…”

“…Restoring the enzymatic activities associated with respiratory chain, decreasing mitochondrial ROS production and inhibition of HSCs activation; 2. Upregulating mitophagy and mitochondrial biogenesis in mice 103 Liver Dihydroartemisinin Promoting HSCs apoptosis via mitochondrial pathway and down-regulating PI3K/Akt 105 Liver PARP inhibition Ameliorating the abnormal ETC and improving the activation of complexes I and IV 102 Liver Melatonin Up-regulating PINK1 and down-regulating LC3-II/LC3 ratio to promote mitophagy 105 Liver Deletion of BCL-B Activates excessive mitophagy to promote apoptosis of HSCs 124 Skin/radiation-induced skin injury JP4-039 (a mitochondrially targeted antioxidant) 1. Acting as a ROS scavenger with the significant affinity for mitochondrial inner membrane; 2.…”