An increase in life expectancy has been accompanied by a larger number of patients with liver diseases that require surgical resection. The aged liver has significantly less reparative capacity following ischemia/ reperfusion (I/R) injury associated with this operation. Innovative approaches are urgently needed to reduce the age-dependent reperfusion injury and improve liver function of elderly patients following surgery. Mitochondrial dysfunction is the major mechanism precipitating lethal I/R injury to liver. Mitochondrial autophagy (mitophagy) is the cellular process that selectively removes abnormal mitochondria. The contribution of mitophagy to the age-dependent liver injury after warm ischemia is unknown. The goal of this study is to elucidate the mechanisms underlying the age-mediated lethal I/R injury to liver and to develop therapeutic strategies to improve liver function in the elderly patients after I/R. Our preliminary data demonstrate that the increased sensitivity of liver to I/R injury with age is strongly associated with its decreased mitophagic responsiveness. Preliminary results show that calpain-2-mediated loss of Atg4B, a key enzyme catalyzing the formation and recycling of autophagosomes, contributes to the age-dependent sensitivity of liver to I/R injury and mitochondrial dysfunction. In addition, we demonstrate that overexpression of Atg4B in both in vitro and in vivo models of I/R mitigates Atg4B loss, mitochondrial dysfunction and cell death. Thus, we propose that restoration or enhancement of mitophagy in aged liver will promote the clearance of dysfunctional mitochondria and consequently ameliorate liver dysfunction and bioenergetic failure after reperfusion. Our principal hypothesis is that defective or insufficient mitophagy is responsible for the increased sensitivity of old liver to lethal I/R injury. Two experimental models will be explored in this application using three different ages of mice. First, isolated hepatocytes will be utilized to determine the mechanisms of age-dependent mitophagic defects after I/R. Second, anesthetized mice will be employed to confirm and extend our I/R findings from an in vitro to an in vivo model. Finally, we will test the potential for mitophagy enhancing agents as therapeutic strategies to improve liver function after I/R in vivo. These studies provide critical mechanistic insights into the age-dependent I/R injury to liver, and will establish novel therapeutic approaches for improving I/R-mediated liver failure in the elderly patients.

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. The liver from the elderly patients has significantly less reparative capacity following I/R injury associated with these operations. To date, there is no therapeutic strategy to reduce lethal I/R injury in the elderly patients. Thus, innovative approaches are urgently needed to reduce the age-dependent reperfusion injury and improve liver function of elderly patients following surgeries. Better understanding of the mechanisms underlying I/R injury would establish novel therapeutic approaches for improving liver function after liver surgery.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Sherker, Averell H
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University of Florida
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Kim, Kyu Min; Han, Chang Yeob; Kim, Ji Young et al. (2018) G?12 overexpression induced by miR-16 dysregulation contributes to liver fibrosis by promoting autophagy in hepatic stellate cells. J Hepatol 68:493-504
Picca, Anna; Mankowski, Robert T; Burman, Jonathon L et al. (2018) Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol 15:543-554
Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) Carbon Monoxide Inhibits Islet Apoptosis via Induction of Autophagy. Antioxid Redox Signal 28:1309-1322
Chun, Sung Kook; Lee, Sooyeon; Flores-Toro, Joseph et al. (2018) Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers. Aging Cell :e12761
Cho, Joonseok; Zhang, Yujian; Park, Shi-Young et al. (2017) Mitochondrial ATP transporter depletion protects mice against liver steatosis and insulin resistance. Nat Commun 8:14477
Chun, Sung Kook; Lee, Sooyeon; Yang, Ming-Jim et al. (2017) Exercise-Induced Autophagy in Fatty Liver Disease. Exerc Sport Sci Rev 45:181-186
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Biel, T G; Lee, S; Flores-Toro, J A et al. (2016) Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner. Cell Death Differ 23:279-90
Chun, Sung Kook; Go, Kristina; Yang, Ming-Jim et al. (2016) Autophagy in Ischemic Livers: A Critical Role of Sirtuin 1/Mitofusin 2 Axis in Autophagy Induction. Toxicol Res 32:35-46
Law, Mary E; Ferreira, Renan B; Davis, Bradley J et al. (2016) CUB domain-containing protein 1 and the epidermal growth factor receptor cooperate to induce cell detachment. Breast Cancer Res 18:80

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