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

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, I. Zendejas, K. E. Behrns, J. S. Kim

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

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.

Original languageEnglish
Pages (from-to)279-290
Number of pages12
JournalCell Death and Differentiation
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2016

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