Open AccessLoss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers
Author(s) -
Chun Sung Kook,
Lee Sooyeon,
FloresToro Joseph,
U Rebecca Y.,
Yang MingJim,
Go Kristina L.,
Biel Thomas G.,
Miney Catherine E.,
Pierre Louis Schiley,
Law Brian K.,
Law Mary E.,
Thomas Elizabeth M.,
Behrns Kevin E.,
Leeuwenburgh Christiaan,
Kim JaeSung
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12761
Subject(s) - autophagy , mitophagy , sirtuin 1 , biology , ischemia , sirtuin , programmed cell death , mitochondrial permeability transition pore , reperfusion injury , mitochondrion , liver injury , liver transplantation , medicine , necrosis , endocrinology , transplantation , andrology , microbiology and biotechnology , apoptosis , biochemistry , genetics , downregulation and upregulation , gene , acetylation
Summary Ischemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age‐mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 ( SIRT 1) and mitofusin 2 ( MFN 2) are affected by I/R in aged livers. Young (3 months) and old (23–26 months) male C57/ BL 6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near‐complete loss of both SIRT 1 and MFN 2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT 1 or MFN 2 alone in old hepatocytes failed to mitigate I/R injury, while co‐overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT 1 deacetylated K655 and K662 residues in the C‐terminus of MFN 2, leading to autophagy activation. The SIRT 1‐ MFN 2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.