Autophagy in liver injury

PROJECT SUMMARY/ABSTRACT Ischemia/reperfusion (I/R) injury in the liver occurs during liver resection and transplantation. Steatotic livers are highly susceptible to I/R injury than lean livers. No therapeutic strategies are currently available to attenuate I/R injury in the patients with steatotic livers. mitoNEET (mNT) is an evolutionarily conserved mitochondrial outer membrane protein containing a unique 2Fe-2S cluster that is tetrahedrally coordinated by 3 Cysteine and 1 Histidine. This small mitochondrial protein regulates redox, bioenergetics, iron homeostasis and autophagy, all of which are indispensable in liver survival after I/R. It is unknown how hepatic mNT is affected by steatosis and I/R. In this application, we will test the hypothesis that the accumulation of nonfunctional mNT sensitizes steatotic livers to I/R injury. Here we have the three independent but complementary Aims. In Aim 1, we will use mouse hepatocytes to investigate molecular mechanisms behind heightened I/R injury in steatotic livers. In Aim 2, we will extend in vitro findings from isolated mouse hepatocytes to an in vivo model of mouse hepatic I/R. In Aim 3, using discarded human livers, we will investigate molecular mechanisms and test the efficacy and safety of potential therapeutic strategies.