Research Paper Volume 10, Issue 8 pp 1902—1920
Aging aggravates hepatic ischemia-reperfusion injury in mice by impairing mitophagy with the involvement of the EIF2α-parkin pathway
- 1 Department of Liver Surgery and Liver Transplantation, Guangzhou Clinical Research and Translation Center for Liver Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- 2 Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong 510630, China
- 3 Department of Biotherapy, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong 510630, China
- 4 Guangdong Key laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong 510630, China
received: July 5, 2018 ; accepted: July 28, 2018 ; published: August 8, 2018 ;https://doi.org/10.18632/aging.101511
How to Cite
Copyright: Li et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.