Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner

被引：93

作者：

Biel, T. G. ^{[1
]}

Lee, S. ^{[1
]}

Flores-Toro, J. A. ^{[1
]}

Dean, J. W. ^{[1
]}

Go, K. L. ^{[1
]}

Lee, M-H ^{[1
]}

Law, B. K. ^{[2
]}

Law, M. E. ^{[2
]}

Dunn, W. A., Jr. ^{[3
]}

Zendejas, I. ^{[1
]}

Behrns, K. E. ^{[1
]}

Kim, J-S ^{[1
,2
,3
]}

机构：

[1] Univ Florida, Dept Surg, Gainesville, FL 32610 USA

[2] Univ Florida, Dept Pharmacol & Therapeut, Gainesville, FL 32610 USA

[3] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA

来源：

CELL DEATH AND DIFFERENTIATION | 2016年 / 23卷 / 02期

基金：

美国国家卫生研究院;

关键词：

PROTEIN HYPERACETYLATION; PERMEABILITY TRANSITION; AUTOPHAGY; ACETYLATION; METABOLISM; MICE; ISCHEMIA/REPERFUSION; HEPATOCYTES; PGC-1-ALPHA; ACTIVATION;

D O I：

10.1038/cdd.2015.96

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. The role of Sirtuin 1 (SIRT1) in hepatic I/R injury remains elusive. Using human and mouse livers, we investigated the effects of I/R on hepatocellular SIRT1. SIRT1 expression was significantly decreased after I/R. Genetic overexpression or pharmacological activation of SIRT1 markedly suppressed defective autophagy, onset of the mitochondrial permeability transition, and hepatocyte death after I/R, whereas SIRT1-null hepatocytes exhibited increased sensitivity to I/R injury. Biochemical approaches revealed that SIRT1 interacts with mitofusin-2 (MFN2). Furthermore, MFN2, but not MFN1, was deacetylated by SIRT1. Moreover, SIRT1 overexpression substantially increased autophagy in wild-type cells, but not in MFN2-deficient cells. Thus, our results demonstrate that the loss of SIRT1 causes a sequential chain of defective autophagy, mitochondrial dysfunction, and hepatocyte death after I/R.

引用

页码：279 / 290

页数：12

共 35 条

[1]

Anderson KA, 2012, ESSAYS BIOCHEM, V52, P23, DOI [10.1042/BSE0520023, 10.1042/bse0520023]

[2] Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development [J].