Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice.

Abstract

BACKGROUND & AIMS:

As life expectancy increases, there are greater numbers of patients with liver diseases who require surgery or transplantation. Livers of older patients have significantly less reparative capacity following ischemia and reperfusion (I/R) injury, which occurs during these operations. There are no strategies to reduce the age-dependent I/R injury. We investigated the role of autophagy in the age dependence of sensitivity to I/R injury.

METHODS:

Hepatocytes and livers from 3- and 26-month-old mice were subjected to in vitro and in vivo I/R, respectively. We analyzed changes in autophagy-related proteins (Atg). Mitochondrial dysfunction was visualized using confocal and intravital multi-photon microscopy of isolated hepatocytes and livers from anesthetized mice, respectively.

RESULTS:

Immunoblot, autophagic flux, genetic, and imaging analyses all associated the increase in sensitivity to I/R injury with age with decreased autophagy and subsequent mitochondrial dysfunction due to calpain-mediated loss of Atg4B. Overexpression of either Atg4B or Beclin-1 recovered Atg4B, increased autophagy, blocked the onset of the mitochondrial permeability transition, and suppressed cell death after I/R in old hepatocytes. Coimmunoprecipitation analysis of hepatocytes and Atg3-knockout cells showed an interaction between Beclin-1 and Atg3, a protein required for autophagosome formation. Intravital multi-photon imaging revealed that overexpression of Beclin-1 or Atg4B attenuated autophagic defects and mitochondrial dysfunction in livers of older mice after I/R.

CONCLUSIONS:

Loss of Atg4B in livers of old mice increases their sensitivity to I/R injury. Increasing autophagy might ameliorate liver damage and restore mitochondrial function after I/R.

• Authors: Jin-Hee Wang, In-Sook Ahn, Trevan D Fischer, Jae-Il Byeon, William A Dunn Jr, Kevin E Behrns, Christiaan Leeuwenburgh, Jae-Sung Kim
• Journal: Gastroenterology (Gastroenterology) Vol. 141 Issue 6 Pg. 2188-2199.e6 (Dec 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 21854730 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Autophagy-Related Proteins
• Beclin-1
• Becn1 protein, mouse
• Atg4b protein, mouse
• Cysteine Endopeptidases

Topics

• Age Factors
• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (physiology)
• Autophagy-Related Proteins
• Beclin-1
• Cysteine Endopeptidases (metabolism)
• Hepatocytes (pathology)
• Immunoblotting
• Immunoprecipitation
• Liver Diseases (metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Microscopy, Confocal
• Microscopy, Fluorescence, Multiphoton
• Reperfusion Injury (metabolism, prevention & control)