Skip Navigation



Human Molecular Genetics Advance Access published online on September 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi341
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrowOA All Versions of this Article:
14/20/3079    most recent
ddi341v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Palmieri, L.
Right arrow Articles by Zeviani, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Palmieri, L.
Right arrow Articles by Zeviani, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press. All rights reserved. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received July 15, 2005
Revised August 30, 2005
Accepted September 7, 2005

Article

Complete loss of function of the heart/muscle specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy

Luigi Palmieri 1, Simona Alberio 2, Isabella Pisano 3, Tiziana Lodi 4, Mija Meznaric-Petrusa 5, Janez Zidar 5, Antonella Santoro 1, Pasquale Scarcia 3, Flavia Fontanesi 4, Eleonora Lamantea 2, Iliana Ferrero 4, and Massimo Zeviani 6*

1 Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy; CNR Institute of Biomembranes and Bioenergetics, 70125 Bari, Italy
2 Division of Molecular Neurogenetics, National Neurological Institute "C. Besta", 20126 Milano, Italy
3 Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70125 Bari, Italy
4 Department of Genetics Anthropology Evolution, University of Parma, 43100 Parma, Italy
5 Department of Neurology, University Medical Centre, Ljubljana, Slovenia
6 Divisione di Neurogenetica Molecolare, Istituto Nazionale Neurologico Carlo Besta, Via Temolo 4, 20126 Milano, Italy

* To whom correspondence should be addressed.
Massimo Zeviani, E-mail: zeviani{at}istituto-besta.it


  Abstract

Multiple mitochondrial DNA deletions are associated with clinically heterogeneous disorders transmitted as mendelian traits. Dominant missense mutations were found in the gene encoding the heart and skeletal muscle-specific isoform of the adenine nucleotide translocator (ANT1) in families with autosomal dominant PEO and in a sporadic patient. We herein report on a sporadic patient who presented with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance and lactic acidosis, but no ophthalmoplegia. A muscle biopsy showed the presence of numerous ragged red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. Molecular analysis revealed a C to A homozygous mutation at nucleotide 368 of the ANT1 gene. The mutation converted a highly conserved alanine into an aspartic acid at codon 123 and was absent in 500 control individuals. This is the first report of a recessive mutation in the ANT1 gene. The clinical and biochemical features are different from those found in dominant ANT1 mutations, resembling those described in ANT1 KO mice. No ATP uptake was measured in proteoliposomes reconstituted with protein extracts from the patient's muscle. The equivalent mutation in AAC2, the yeast ortholog of human ANT1, resulted in a complete loss of transport activity and in the inability to rescue the severe OXPHOS phenotype displayed by WB-12, an AAC1/AAC2 defective strain. Interestingly, exposure to reactive oxygen species scavengers dramatically increased the viability of the WB-12 transformant, suggesting that increased redox stress is involved in the pathogenesis of the disease and that anti-ROS therapy may be beneficial to patients.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 GeneticsHome page
R. El-Khoury and A. Sainsard-Chanet
Suppression of Mitochondrial DNA Instability of Autosomal Dominant Forms of Progressive External Ophthalmoplegia-Associated ANT1 Mutations in Podospora anserina
Genetics, November 1, 2009; 183(3): 861 - 871.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
D. C. Wallace and W. Fan
The pathophysiology of mitochondrial disease as modeled in the mouse
Genes & Dev., August 1, 2009; 23(15): 1714 - 1736.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Fiermonte, E. Paradies, S. Todisco, C. M. T. Marobbio, and F. Palmieri
A Novel Member of Solute Carrier Family 25 (SLC25A42) Is a Transporter of Coenzyme A and Adenosine 3',5'-Diphosphate in Human Mitochondria
J. Biol. Chem., July 3, 2009; 284(27): 18152 - 18159.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
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]

Home page
 JCBHome page
S. M. Claypool, Y. Oktay, P. Boontheung, J. A. Loo, and C. M. Koehler
Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane
J. Cell Biol., September 9, 2008; 182(5): 937 - 950.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
I. I. Pipinos, S. A. Swanson, Z. Zhu, A. A. Nella, D. J. Weiss, T. L. Gutti, R. D. McComb, B. T. Baxter, T. G. Lynch, and G. P. Casale
Chronically ischemic mouse skeletal muscle exhibits myopathy in association with mitochondrial dysfunction and oxidative damage
Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2008; 295(1): R290 - R296.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. V. Brower, N. Rodic, T. Seki, M. Jorgensen, N. Fliess, A. T. Yachnis, J. R. McCarrey, S. P. Oh, and N. Terada
Evolutionarily Conserved Mammalian Adenine Nucleotide Translocase 4 Is Essential for Spermatogenesis
J. Biol. Chem., October 5, 2007; 282(40): 29658 - 29666.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
E. Baruffini, T. Lodi, C. Dallabona, A. Puglisi, M. Zeviani, and I. Ferrero
Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans
Hum. Mol. Genet., October 1, 2006; 15(19): 2846 - 2855.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.