Sirtuin 1 Suppresses Mitochondrial Dysfunction of Ischemic Mouse Livers in a Mitofusin 2-dependent Manner

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2015 Jul 18

PMID 26184910

Citations 59

Authors

T G Biel

S Lee

J A Flores-Toro

J W Dean

K L Go

M-H Lee

B K Law

M E Law

W A Dunn Jr

I Zendejas

K E Behrns

J-S Kim

Affiliations

Soon will be listed here.

Abstract

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.

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