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.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Wang JH,Ahn IS,Fischer TD,Byeon JI,Dunn WA Jr,Behrns KE,Leeuwenburgh C,Kim JSdoi
10.1053/j.gastro.2011.08.005subject
Has Abstractpub_date
2011-12-01 00:00:00pages
2188-2199.e6issue
6eissn
0016-5085issn
1528-0012pii
S0016-5085(11)01153-Xjournal_volume
141pub_type
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