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Sirtuin 1 induces autophagy to suppress liver ischemia/reperfusion injury in mice (1115.1)
Author(s) -
Biel Thomas,
FloresToro Joseph,
Dean Joseph,
Law Brain,
Zendejas Ivan,
Behrns Kevin,
Kim JaeSung
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1115.1
Subject(s) - autophagy , sirt3 , sirtuin 1 , mitochondrial permeability transition pore , sirtuin , microbiology and biotechnology , mitochondrion , reperfusion injury , calpain , mitophagy , nad+ kinase , liver injury , ischemia , in vivo , biology , chemistry , apoptosis , programmed cell death , biochemistry , pharmacology , medicine , downregulation and upregulation , enzyme , gene
Autophagy clears dysfunctional proteins and organelles in a timely manner. Defective autophagy and subsequent mitochondrial dysfunction is a key mechanism of I/R injury to the liver. Sirtuin 1 (SIRT1) is an NAD + ‐dependent deacetylase that induces longevity and stress resistance, but the role of SIRT1 in hepatic I/R is unknown. Immunoblotting analysis after in vivo I/R of human and mouse livers and simulated in vitro I/R of mouse hepatocytes revealed that ischemia decreases SIRT1 to less than 20% of normal values, which is not recovered by reperfusion. I/R, however, did not decrease the expression of mitochondrial sirtuins such as SIRT3 and 5. Biochemical analysis showed that SIRT1 depletion during I/R is mediated by multiple proteases, including calpains. Specific overexpression of SIRT1 mitigated defective mitochondrial autophagy, onset of the mitochondrial permeability transition, and subsequent hepatocyte death after both in vitro and in vivo I/R. In striking contrast, hepatocytes from SIRT1 knockout mice were significantly susceptible to I/R injury. Thus, our results suggest that SIRT1 suppresses I/R injury in the liver by enhancing mitochondrial autophagy. Grant Funding Source : NIH DK079879, DK090115, EY019688, HL064024 and AG028740