Mitochondrial dysfunction is the major mechanism precipitating ischemia/reperfusion (I/R) injury which commonly occurs during liver surgery, trauma, hemorrhagic shock and liver transplantation. Mitochondrial autophagy (mitophagy) is the only cellular process that selectively removes abnormal mitochondria. The contribution of mitophagy to liver injury after warm ischemia is unknown. The goal of this study is to elucidate the mechanisms underlying lethal I/R injury to liver and to develop therapeutic strategies to improve liver function after I/R. In preliminary studies, we observed the loss of Atg7 and Beclin-1, key mitophagy proteins, after I/R. We have shown that Ca2+ overloading after I/R stimulates calpain isoform-2 and that activated calpain-2 degrades Atg7 and Beclin-1. Suppression of mitophagy protein depletion prevents onset of the mitochondrial permeability transition (MPT), hepatocellular necrosis and apoptosis, and protects mitochondrial function after I/R. Furthermore, we noted that loss of mitophagy proteins occurs in an in vivo model of hepatic I/R in mice, concomitant with mitochondrial depolarization and cell death. We propose that I/R impairs mitophagy, which in turn leads to accumulation of dysfunctional mitochondria and ultimately hepatic failure. Therefore, restoration or enhancement of mitophagy in ischemic liver will promote the clearance of dysfunctional mitochondria and consequently ameliorate liver dysfunction after reperfusion. Our principle hypothesis is that Ca2+ overloading causes increased calpain-2 activity that subsequently results in hydrolyzation of key mitophagy proteins leading to impaired mitophagy and MPT-dependent hepatocyte death after I/R. These studies provide critical mechanistic insights into lethal I/R injury to liver, and will establish novel therapeutic approaches for improving I/R-mediated liver failure.

Public Health Relevance

Impairment of blood flow causes a tissue ischemia and recovery of blood flow causes reperfusion injury to liver. Ischemia/reperfusion (I/R) injury is a causative factor of morbidity and mortality during liver resection, hemorrhagic shock, cardiovascular surgery with extracorporeal circulation, transplantation and abdominal compartment syndrome. I/R injury remains a fundamental complication of hepatic surgery, and patients with preexisting liver diseases that often require inflow occlusion are more likely to develop severe postoperative I/R injury. Better understanding of the mechanisms underlying ischemia/reperfusion injury would establish novel therapeutic approaches for improving liver function after liver surgery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079879-05
Application #
8401170
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (02))
Program Officer
Sherker, Averell H
Project Start
2009-03-05
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$296,433
Indirect Cost
$90,722
Name
University of Florida
Department
Surgery
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Akin, Debra; Wang, S Keisin; Habibzadegah-Tari, Pouran et al. (2014) A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10:
Fischer, Trevan D; Wang, Jin-Hee; Vlada, Adrian et al. (2014) Role of autophagy in differential sensitivity of hepatocarcinoma cells to sorafenib. World J Hepatol 6:752-8
Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58
Kim, Jae-Sung; Wang, Jin-Hee; Biel, Thomas G et al. (2013) Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers. Toxicol Appl Pharmacol 273:600-10
Dutta, Debapriya; Xu, Jinze; Kim, Jae-Sung et al. (2013) Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity. Autophagy 9:328-44
Park, Bonggoo; Lee, Yong-Moon; Kim, Jae-Sung et al. (2013) Neutral sphingomyelinase 2 modulates cytotoxic effects of protopanaxadiol on different human cancer cells. BMC Complement Altern Med 13:194
Law, M E; Corsino, P E; Jahn, S C et al. (2013) Glucocorticoids and histone deacetylase inhibitors cooperate to block the invasiveness of basal-like breast cancer cells through novel mechanisms. Oncogene 32:1316-29
Wang, Jin-Hee; Behrns, Kevin E; Leeuwenburgh, Christiaan et al. (2012) Critical role of autophage in ischemia/reperfusion injury to aged livers. Autophagy 8:140-1
Kim, Jae-Sung; Wang, Jin-Hee; Lemasters, John J (2012) Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation: role of Ca2+-dependent mitochondrial formation of reactive oxygen species. Am J Physiol Gastrointest Liver Physiol 302:G723-31
Wang, Jin-Hee; Ahn, In-Sook; Fischer, Trevan D et al. (2011) Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice. Gastroenterology 141:2188-2199.e6

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