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"The Role of Mitochondrial Permeability Transition Pore in Alcoholic Liver Disease"

by
Guoqiang Wang
Pharmacology and Physiology Program
M.S. 2006, Nanjing University, China
B.S. 2003, Ludong University, China


Thesis Advisor: Lawrence D. Gaspers, Ph.D.
Associate Professor
Department of Pharmacology and Physiology

Tuesday, June 17, 2014
12:00 P.M., MSB H-609B


Abstract

Adaptive change has been proposed to underlie the onset and pathogenesis of alcoholic liver diseases. In this thesis research project, we have observed an adaptive change in the activation of the Ca2+-induced mitochondrial permeability transition pore (mPTP). The prolonged opening of the “pore” has been proposed to regulate some types of cell death, whereas transient opening of the “pore” may be an important regulator of mitochondrial metabolism. In our hands, the mPTP is desensitized in rat hepatocytes after long-term ethanol feeding. These effects are correlated with up regulation of mitochondrial heat shock proteins and an increased efficacy for ATP to inhibit the Ca2+-induced permeability transition. These adaptive responses to alcohol-induced stress may be the reason causing a desensitization of the mPTP. The lower opening probability of mPTP increases the rate of mitochondrial Ca2+ accumulation in hepatocytes isolated from ethanol-fed rats compared to their pair-fed controls. Moreover, it is also correlated with an increased in total mitochondrial Ca2+ levels, which might be involved in remodeling mitochondrial metabolism in hepatocytes from ethanol-fed rats.
The regulation of mPTP by adenine nucleotides was also examined in this thesis research project. We have found that mPTP could be closed by either ATP or ADP, but the effect of ADP is strongly dependent on conversion to ATP. Moreover, Ca2+-induced mitochondrial swelling and changes in mitochondrial structure could be reversed by exogenously added ATP. These effects on mitochondrial morphology occurred even in the absence of a mitochondrial membrane potential. These data indicate that ATP can directly stimulate remodeling of mitochondrial structure and reverse mitochondrial swelling. Surprisingly, Ca2+-induced swelling could be reversed by the addition of AMP plus CsA, while neither AMP nor CsA treatments were effective alone. Finally, adenine nucleotides, but not CsA, effectively blocked the rapid and spontaneous release of matrix Ca2+ from Ca2+-overloaded and depolarized mitochondria. Taken together, these data suggest that binding of adenine nucleotides to the mPTP may alter the Ca2+ transport properties of channel, in addition to modulating the opening state of the pore and the remodeling of mitochondrial structure.


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