Abstract
Hepatic ischemia-reperfusion (I/R) injury fundamentally influences the performance of aged liver grafts. The significance of mitophagy in the age dependence of sensitivity to I/R injury remains poorly understood. Here, we show that aging aggravated hepatic I/R injury with decreased mitophagy in mice. The enhancement of mitophagy resulted in significant protection against hepatic I/R injury. Parkin, an E3 ubiquitin ligase, was found depleted by I/R in aged livers. In oxygen-glucose deprivation reperfusion (OGD-Rep.)-treated L02 cells, parkin silencing impaired mitophagy and aggravated cell damage through a relative large mitochondrial membrane potential transition. The phosphorylation of the endoplasmic reticulum stress response protein EIF2α, which was also reduced in the aged liver, induced parkin expression both in vivo and vitro. Forty-six hepatic biopsy specimens from liver graft were collected 2 hours after complete revascularization, followed by immunohistochemical analyses. Parkin expression was negatively correlated to donor age and the peak level of aspartate aminotransferase within first week after liver transplantation. Our translational study demonstrates that aging aggravated hepatic I/R injury by impairing the age-dependent mitophagy function via an insufficient parkin expression and identifies a new strategy to evaluate the capacity of an aged liver graft in the process of I/R through the parkin expression.
Highlights
Hepatic ischemia/reperfusion (I/R) is one of the leading causes of liver injury during liver transplantation [1]
Hepatic I/R injury profoundly influences the burden of liver diseases
We demonstrated that defective mitophagy, as a consequence of parkin and Atg5 reduction, is a causal mechanism for the age-dependent hepatic I/R injury (Fig. 8D) and the induction of parkin expression by www.aging‐us.com maintaining the phosphorylation of EIF2α has a therapeutic potential for ameliorating the age-mediated hepatic I/R injury
Summary
Hepatic ischemia/reperfusion (I/R) is one of the leading causes of liver injury during liver transplantation [1]. Aged donation after cardiac death (DCD) has been proposed as a means of increasing the pool of liver grafts with the aging tendency of the population [2]. The aged liver has a significantly decreased compensatory capacity following I/R. The evaluation of the capacity is always a challenge because of an incomplete www.aging‐us.com understanding of the mechanism by which aging increases the sensitivity of the liver to the I/R injury. Damaged mitochondria compromise the energy metabolism and produce excessive reactive oxygen species (ROS) and release pro-apoptotic factors, which may lead to hepatocyte death. The maintenance of a cohort of healthy mitochondria is crucial for the homeostasis and viability of hepatocytes in hepatic I/R
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