Mitochondrial dysfunction is a major cause of liver pathology by participating in oxidative stress and cell death. Mitochondria continually change their morphology and location inside the cell. Dynamic changes in mitochondrial morphology involve mainly fission and fusion of mitochondrial tubules. However, the functional significance of the dynamic behavior of mitochondria is not well understood. The mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species (ROS) that contributes to oxidative stress conditions. Our studies have demonstrated that inhibiting mitochondrial fission decreases cellular ROS levels in ROS-overproducing conditions, which in turn reduces oxidative stress-induced cell death. Our long-term objectives are to elucidate molecular mechanisms of mitochondrial fission/fusion, and to define the physiological roles of mitochondrial dynamics. In this application, we will continue to study the molecular mechanisms of how mitochondrial fission and fusion proteins control mitochondrial morphology, and investigate the role of mitochondrial dynamics in mitochondrial activity and liver function. The central hypothesis of this proposal is that networks of molecular interactions involving fission and fusion proteins on the mitochondrial membrane regulate mitochondrial morphology and function, and play an integral role in health and pathology of the liver. In the first specific aim, we will study the molecular mechanisms that control the fission/fusion balance of mitochondria. In the second specific aim, we will investigate the involvement of the mitochondrial fission protein hFis1 in mitochondrial fission and apoptosis. The third specific aim is to understand the physiological significance of mitochondrial morphology by focusing on its relationship with the ETC activity and ROS generation in hepatocytes. We will also test whether mitochondrial fission can be a useful target to control liver injury using a cholestatic liver model how mitochondrial dynamics contribute to the regulation of mitochondrial function and cell physiology in health and diseases of the liver.

Public Health Relevance

Growing evidence indicates that control of mitochondrial morphology is a fundamental cellular process determining cell life and death, and we believe that information from these studies will greatly increase our understanding of how mitochondrial dynamics contribute to the regulation of mitochondrial function and cell physiology in health and diseases of the liver.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061991-10
Application #
8425088
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Serrano, Jose
Project Start
2002-07-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$237,882
Indirect Cost
$79,294
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Lee, Hakjoo; Yoon, Yisang (2014) Transient contraction of mitochondria induces depolarization through the inner membrane dynamin OPA1 protein. J Biol Chem 289:11862-72
Lee, Hakjoo; Yoon, Yisang (2014) Mitochondrial fission: regulation and ER connection. Mol Cells 37:89-94
Galloway, Chad A; Lee, Hakjoo; Brookes, Paul S et al. (2014) Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 307:G632-41
Jhun, Bong Sook; Lee, Hakjoo; Jin, Zheng-Gen et al. (2013) Glucose stimulation induces dynamic change of mitochondrial morphology to promote insulin secretion in the insulinoma cell line INS-1E. PLoS One 8:e60810
Yoon, Yisang; Galloway, Chad A; Jhun, Bong Sook et al. (2011) Mitochondrial dynamics in diabetes. Antioxid Redox Signal 14:439-57
Huang, Pinwei; Galloway, Chad A; Yoon, Yisang (2011) Control of mitochondrial morphology through differential interactions of mitochondrial fusion and fission proteins. PLoS One 6:e20655
Yu, Tianzheng; Jhun, Bong Sook; Yoon, Yisang (2011) High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission. Antioxid Redox Signal 14:425-37
Cui, Mei; Tang, Xiangna; Christian, Whitney V et al. (2010) Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. J Biol Chem 285:11740-52
Hom, Jennifer; Yu, Tianzheng; Yoon, Yisang et al. (2010) Regulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes. Biochim Biophys Acta 1797:913-21
Serasinghe, Madhavika N; Yoon, Yisang (2008) The mitochondrial outer membrane protein hFis1 regulates mitochondrial morphology and fission through self-interaction. Exp Cell Res 314:3494-507

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