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.
Highlights
Hepatic fibrosis is an outcome of many chronic liver diseases that is characterized by the excessive deposition of extracellular matrix proteins, especially collagen I, in the liver[1]
The Mitochondrial DNA (mtDNA) and the expression of the mitochondrial protein TOM20 were increased by 6 weeks of the CCl4 treatment, indicating that mitophagy was reduced during hepatic fibrosis
Mitophagy is the main pathway by which injured mitochondria are cleared and plays a vital role in maintaining mitochondrial homeostasis, which is critical for apoptosis[7]
Summary
Hepatic fibrosis is an outcome of many chronic liver diseases that is characterized by the excessive deposition of extracellular matrix proteins, especially collagen I, in the liver[1]. The activation of hepatic stellate cells (HSCs) is a key event in hepatic fibrosis since activated HSCs are the major source of collagen I2. HSCs undergo apoptosis during fibrosis reversal[3]. The clearance of activated HSCs by apoptosis is critical for the reversibility of fibrosis[4]. There are two major apoptosis signaling pathways, i.e., the extrinsic pathway and the intrinsic pathway. The intrinsic apoptotic pathway, which is called the mitochondrial apoptotic pathway, is triggered by mitochondrial outer membrane permeabilization (MOMP) in response to intracellular stressors. MOMP, which is regulated by members of the BCL-2 family, stimulates the formation of the apoptosome, which, in turn, results in cell death[5]
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