Journal
AGING-US
Volume 10, Issue 8, Pages 1902-1920Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.101511
Keywords
aged graft; hepatic ischemia reperfusion injury; mitophagy; graft evaluation; parkin
Categories
Funding
- National Natural Science Foundation of China [81600505, 81770648, 81670601, 81570593, 81370555]
- National Key RD Plan [2017YFA0104304]
- Key Scientific and Technological Projects of Guangdong Province [2015B020226004, 2017A020215178]
- Guangdong Natural Science Foundation [2015A030312013, 2017A030311034]
- Guangdong Natural Science Fund for Distinguished Young Scholars [S20120011190]
- Science and Technology Planning Project of Guangdong Province [2017B030314027, 2017B020209004]
- Science and Technology Planning Project of Guangzhou [2014Y200544, 201604020001]
- Guangdong Province
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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 EIF2 alpha, 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.
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