Macroautophagy and Chaperone-Mediated Autophagy Are... : Hepatology (original) (raw)
Liver Injury/Regeneration
Macroautophagy and Chaperone-Mediated Autophagy Are Required for Hepatocyte Resistance to Oxidant Stress
1_Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY_
*Address reprint requests to: Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail:[email protected]; fax: 718-430-8975
Received 15 December 2009; accepted 22 February 2010
Supported in part by National Institutes of Health grants DK044234, DK061498, and AG031782.
Published online in Wiley InterScience (www.interscience.wiley.com).
Potential conflict of interest: Nothing to report.
Additional Supporting Information may be found in the online version of this article.
Abstract
The function of the lysosomal degradative pathway of autophagy in cellular injury is unclear, because findings in nonhepatic cells have implicated autophagy as both a mediator of cell death and as a survival response. Autophagic function is impaired in steatotic and aged hepatocytes, suggesting that in these settings hepatocellular injury may be altered by the decrease in autophagy. To delineate the specific function of autophagy in the hepatocyte injury response, the effects of menadione-induced oxidative stress were examined in the RALA255-10G rat hepatocyte line when macroautophagy was inhibited by a short hairpin RNA (shRNA)-mediated knockdown of the autophagy gene atg5 . Loss of macroautophagy sensitized cells to apoptotic and necrotic death from normally nontoxic concentrations of menadione. Loss of macroautophagy led to overactivation of the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway that induced cell death. Death occurred from activation of the mitochondrial death pathway with cellular adenosine triphosphate (ATP) depletion, mitochondrial cytochrome c release, and caspase activation. Sensitization to death from menadione occurred despite up-regulation of other forms of autophagy in compensation for the loss of macroautophagy. Chaperone-mediated autophagy (CMA) also mediated resistance to menadione. CMA inhibition sensitized cells to death from menadione through a mechanism different from that of a loss of macroautophagy, because death occurred in the absence of JNK/c-Jun overactivation or ATP depletion.
Conclusion:
Hepatocyte resistance to injury from menadione-induced oxidative stress is mediated by distinct functions of both macroautophagy and CMA, indicating that impaired function of either form of autophagy may promote oxidant-induced liver injury. Hepatology 2010
© 2010 by Lippincott Williams & Wilkins, Inc.