Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying decreased mitochondrial autophagy, increased apoptosis, impaired DNA damage repair and altered cell cycle distribution

Abstract

Hepatic ischemia/reperfusion injury (HIRI) serves a causative role in postoperative hepatocyte death; however, the mechanisms underlying HIRI remain unclear. Mitochondrial autophagy, with apoptosis, cell cycle distribution and DNA damage repair, may be regarded as a regulatory factor post-HIRI. Parkin, a novel ubiquitin ligase, has been reported to increase mitochondrial autophagy and decrease apoptosis. However, the association between Parkin, mitochondrial autophagy and other regulatory factors in HIRI is unclear. In the present study, the effects of Parkin on HIRI were investigated, using hepatocytes and livers from male Sprague Dawley rats subjected to simulated in vivo HIRI. The results of the present study demonstrated that Parkin expression and mitochondrial autophagy were upregulated post-HIRI, leading to decreased hepatocyte death. Parkin knockdown suppresses the level of mitochondrial autophagy and promotes hepatocyte apoptosis by suppressing apoptosis regulator Bcl-2 function post-HIRI. In addition, Parkin deficiency alters cell cycle distribution and impairs DNA damage repair post-HIRI. In conclusion, Parkin facilitates mitochondrial autophagy and DNA damage repair, inhibits apoptosis, and modulates the cell cycle, leading to increased hepatocyte survival, demonstrating that Parkin may act as a protective regulatory factor post HIRI.

Role and Mechanisms of Mitophagy in Liver Diseases

“…When reperfusion initiates, the reestablishment of the electron transfer chain and ATP synthesis in mitochondria enables autophagy to eliminate abnormal proteins and organelles that are produced during ischemia. Enhanced hepatic mitophagy is observed at the early stages of IR in both in vivo and in vitro models, which is associated with elevated cell death and aggregated liver injury [164][165][166]. However, the autophagy capacity also becomes impaired following prolonged ischemia, which may not be sufficient to eliminate the accumulated dysfunctional mitochondria.…”

Remote Ischemic Preconditioning Attenuates Hepatic Ischemia/Reperfusion Injury after Hemorrhagic Shock by Increasing Autophagy

“…Bone marrow mesenchymal stem cell-derived hepatocyte-like cell Exosomes and ulinastatin have also been proven to reduce hepatocellular apoptosis by enhancing autophagy [26,27]. Reducing mitochondrial autophagy by knocking out PINK can increase hepatic I/RI [28]. Our study demonstrated that in SI/RI-induced secondary liver injury, RIPC increased the expression of autophagy-related proteins, such as LC3 and Beclin-1, and decreased hepatocellular apoptosis, as well as markers of liver injury.…”

Inhibition of excessive mitophagy by N-acetyl-L-tryptophan confers hepatoprotection against Ischemia-Reperfusion injury in rats

“…Mitophagy was reported to promote the clearance of injured mitochondria and then attenuate cell death induced by HIRI. Ning et al (2018) demonstrated that parkin mediated mitochondrial autophagy was upregulated post-HIRI, leading to decreased hepatocyte death. However, parkin deficiency elevates HIRI by decreasing mitochondrial autophagy and increasing apoptosis.…”