Human Molecular Genetics, 2002, Vol. 11, No. 16 1835-1843
© 2002 Oxford University Press
Induction of an unregulated channel by mutations in adenine nucleotide translocase suggests an explanation for human ophthalmoplegia
Molecular Genetics and Evolution Group, Research School of Biological Sciences, The Australian National University, GPO Box 475, Canberra, ACT 2601, Australia
Received March 18, 2002; Accepted June 6, 2002
Adenine nucleotide translocase (Ant) is primarily involved in ATP/ADP exchange across the mitochondrial inner membrane. Recently, the A114P missense mutation in the human Ant1 protein was found to be associated with autosomal dominant progressive external ophthalmoplegia (adPEO). Ant1A114P was proposed to cause an imbalance of the mitochondrial deoxynucleotide pool that subsequently affects the accuracy of mtDNA replication, thereby leading to accumulation of mutant mtDNA. In the present study, it has been shown that the A128P mutation of the Saccharomyces cerevisiae Aac2 protein, equivalent to A114P in human Ant1p, does not always affect respiratory growth. However, expression of aac2 A128P results in depolarization, structural swelling and disintegration of mitochondria, and ultimately an arrest of cell growth in a dominant-negative manner. The aac2 A128P mutation likely induces an unregulated channel allowing free passage of solutes across the inner membrane. These data raise the possibility that the formation of an unregulated channel, rather than a defect in ATP/ADP exchange, is a direct pathogenic factor in human adPEO. The accumulation of mtDNA mutations might be a consequence of mitochondrial dysfunction.
* To whom correspondence should be addressed at: School of Biological Sciences, Nanyang Technological University, 1 Nanyang Walk, Block 5 Level 3, Singapore 637616, Republic of Singapore. Fax: +65 67953261; Email: xjchen{at}ntu.edu.sg
Present address: School of Biological Sciences, Nanyang Technological University, 1 Nanyang Walk, Block 5 Level 3, Singapore 637616, Republic of Singapore.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  X. Wang, K. Salinas, X. Zuo, B. Kucejova, and X. J. Chen Dominant membrane uncoupling by mutant adenine nucleotide translocase in mitochondrial diseases Hum. Mol. Genet., December 15, 2008; 17(24): 4036 - 4044. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Dienhart and R. A. Stuart The Yeast Aac2 Protein Exists in Physical Association with the Cytochrome bc1-COX Supercomplex and the TIM23 Machinery Mol. Biol. Cell, September 1, 2008; 19(9): 3934 - 3943. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dorner, S. Giessen, R. Gaub, H. G. Siestrup, P. L. Schwimmbeck, R. Hetzer, W. Poller, and H.-P. Schultheiss An isoform shift in the cardiac adenine nucleotide translocase expression alters the kinetic properties of the carrier in dilated cardiomyopathy Eur J Heart Fail, January 1, 2006; 8(1): 81 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. J. Chen Sal1p, a Calcium-Dependent Carrier Protein That Suppresses an Essential Cellular Function Associated With the Aac2 Isoform of ADP/ATP Translocase in Saccharomyces cerevisiae Genetics, June 1, 2004; 167(2): 607 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Fontanesi, L. Palmieri, P. Scarcia, T. Lodi, C. Donnini, A. Limongelli, V. Tiranti, M. Zeviani, I. Ferrero, and A. M. Viola Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stability Hum. Mol. Genet., May 1, 2004; 13(9): 923 - 934. [Abstract] [Full Text] [PDF]
|
|