Abstract
Mitophagy affects the activation of hepatic stellate cells (HSCs). Mitochondria-targeted ubiquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces the production of intracellular reactive oxygen species (ROS). However, its relationship with mitophagy remains unclear. This study evaluated mitophagy during HSC activation and the effects of MitoQ on mitophagy in cell culture and in an animal model of the activation of HSCs. We found that MitoQ reduced the activation of HSCs and alleviated hepatic fibrosis. PINK1 (PTEN-induced putative kinase 1) is a putative serine/threonine kinase located in the mitochondria’s outer membrane. While the activation of primary HSCs or LX-2 cells was associated with reduced PINK1/parkin-mediated mitophagy, MitoQ reduced intracellular ROS levels, enhanced PINK1/parkin-mediated mitophagy, and inhibited the activation of HSCs. After knocking down the key mitophagy-related protein, PINK1, in LX-2 cells to block mitophagy, MitoQ intervention failed to inhibit HSC activation. Our results showed that MitoQ inhibited the activation of HSCs and alleviated hepatic fibrosis by enhancing PINK1/parkin-mediated mitophagy.
Highlights
Hepatic fibrosis is a common scarring response to chronic liver injury caused by various etiological factors, including viral hepatitis, alcohol abuse, autoimmune hepatitis, and nonalcoholic steatohepatitis
Mitochondriatargeted ubiquinone (MitoQ) intervention significantly reduced the ALT and AST levels (Fig 1e, f). These findings showed that MitoQ alleviated liver damage and liver fibrosis
PINK1/parkin-mediated mitophagy plays an important role in autophagy-dependent mitochondrial degradation in mammals
Summary
Hepatic fibrosis is a common scarring response to chronic liver injury caused by various etiological factors, including viral hepatitis, alcohol abuse, autoimmune hepatitis, and nonalcoholic steatohepatitis. The degree of fibrosis is measured by semiquantitative scoring, such as the Ishak score [1]. Activation of hepatic stellate cells (HSCs) is a key step in the development of hepatic fibrosis. Resident HSCs become fibrogenic myofibroblast when they are activated, expressing α-SMA and producing large amounts of extracellular matrix proteins, such as collagen 1, leading to hepatic fibrosis. HSCs are activated by a variety of growth factors and cytokines, including transforming growth factor-β (TGF-β) [2,3]. Inhibiting HSC activation could be an effective strategy for treating liver fibrosis
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