Mitochondrial dysfunction promotes aging, cell death, and ultimately, functional failure and degeneration of the cell. One of the examples is autosomal dominant progressive external ophthalmoplegia (adPEO), an adult-onset neuromuscular degenerative disease caused by mutations in nuclear-encoded proteins, such as the adenine nucleotide translocase isoform 1 (Ant1). Ant1 catalyzes the ADP/ATP exchange across the mitochondrial inner membrane. It is intensively debated that Ant may also play a critical role in the organelle-initiated cell death by participating in the permeabilization of mitochondrial membranes. Our recent investigations have revealed that the pathogenic alleles of Ant1 in adPEO patients cause mitochondrial permeabilization and degenerative cell death in the model yeast system. A parallel study has also indicated that Ant has a novel physiological function distinct from ADP/ATP exchange. We hypothesize that the novel cellular function of Ant is related to a membrane channel, and that a dysregulation of the channel may play a critical role in mitochondrial membrane permeabilization and functional degeneration of adPEO cells. The broad objective of this proposal is to understand the pathogenic mechanism of adPEO and the Ant-induced cell death in general. More specifically, we will (1) determine the mechanism of the Ant-induced cell death, the nature of the Ant-based channel, the origin of the adPEO-associated polydisperse mitochondrial DMA deletions, and the factors (e.g., aging) that affect the onset of the cell death trait in cell populations. (2) We will map the death domains in the Ant molecule and isolate trans-acting elements that modulate the membrane-permeabilizing ability of the mutant Ant. (3) We will test the bifunctionality hypothesis by genetic dissection of Ant molecules from yeast and humans and determine the origin of the pathogenic membrane-permeabilizing channel. The uniqueness of the proposal is the use of the unparalleled yeast system that permits an easy genetic tracking of the cell death mechanism. Identifying the exact pathogenic factor of adPEO could lead to the development of adequate therapeutic strategies for clinical treatment of the disease. Most importantly, success of the proposed studies could contribute to a better understanding of the exact role of Ant in cell death, which in turn, could have a broad applicability to other forms of degenerative disease resulting from excessive cell destruction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG023731-01A1
Application #
6871467
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Sierra, Felipe
Project Start
2005-01-01
Project End
2008-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
1
Fiscal Year
2005
Total Cost
$218,400
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Coyne, Liam P; Chen, Xin Jie (2018) mPOS is a novel mitochondrial trigger of cell death - implications for neurodegeneration. FEBS Lett 592:759-775
Chen, Xin Jie; Clark-Walker, George Desmond (2018) Unveiling the mystery of mitochondrial DNA replication in yeasts. Mitochondrion 38:17-22
Liu, Yaxin; Wang, Xiaowen; Chen, Xin Jie (2015) Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases. Mol Biol Cell 26:1985-94
Wang, Xiaowen; Chen, Xin Jie (2015) A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524:481-4
La, Thuy; Clark-Walker, George Desmond; Wang, Xiaowen et al. (2013) Mutations on the N-terminal edge of the DELSEED loop in either the ? or ? subunit of the mitochondrial F1-ATPase enhance ATP hydrolysis in the absence of the central ? rotor. Eukaryot Cell 12:1451-61
Wang, Xiaowen; Mbantenkhu, MacMillan; Wierzbicki, Sara et al. (2013) Preparation of the Mgm101 recombination protein by MBP-based tagging strategy. J Vis Exp :
Chen, Xin Jie (2013) Mechanism of homologous recombination and implications for aging-related deletions in mitochondrial DNA. Microbiol Mol Biol Rev 77:476-96
Mbantenkhu, MacMillan; Wierzbicki, Sara; Wang, Xiaowen et al. (2013) A short carboxyl-terminal tail is required for single-stranded DNA binding, higher-order structural organization, and stability of the mitochondrial single-stranded annealing protein Mgm101. Mol Biol Cell 24:1507-18
Liu, Yaxin; Chen, Xin Jie (2013) Adenine nucleotide translocase, mitochondrial stress, and degenerative cell death. Oxid Med Cell Longev 2013:146860
Nardozzi, Jonathan D; Wang, Xiaowen; Mbantenkhu, MacMillan et al. (2012) A properly configured ring structure is critical for the function of the mitochondrial DNA recombination protein, Mgm101. J Biol Chem 287:37259-68

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