Human Molecular Genetics Advance Access first published online on October 29, 2009
This version [Corrected Proof] published online on November 12, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp503
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Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells
1 Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA and 2 Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
* To whom correspondence should be addressed at: Weill Medical College of Cornell University, 525 E. 68th St., A-505, New York, NY 10065, USA. Tel: +1 2127464605; Fax: +1 2127468276; Email: gim2004{at}mail.med.cornell.eduNew GenBank accession numbers: GQ891609, GQ891610, GQ891611, GQ891612, GQ891613.
Received July 6, 2009; Revised October 1, 2009; Accepted October 27, 2009
Mutations in the mitochondrial DNA (mtDNA) encoded subunit 6 of ATPase (ATP6) are associated with variable disease expression, ranging from adult onset neuropathy, ataxia and retinitis pigmentosa (NARP) to fatal childhood maternally inherited Leigh's syndrome (MILS). Phenotypical variations have largely been attributed to mtDNA heteroplasmy. However, there is often a discrepancy between the levels of mutant mtDNA and disease severity. Therefore, the correlation among genetic defect, bioenergetic impairment and clinical outcome in NARP/MILS remains to be elucidated. We investigated the bioenergetics of cybrids from five patients carrying different ATP6 mutations: three harboring the T8993G, one with the T8993C and one with the T9176G mutation. The bioenergetic defects varied dramatically, not only among different ATP6 mutants, but also among lines carrying the same T8993G mutation. Mutants with the most severe ATP synthesis impairment showed defective respiration and disassembly of respiratory chain complexes. This indicates that respiratory chain defects modulate the bioenergetic impairment in NARP/MILS cells. Sequencing of the entire mtDNA from the different mutant cell lines identified variations in structural genes, resulting in amino acid changes that destabilize the respiratory chain. Taken together, these results indicate that the mtDNA background plays an important role in modulating the biochemical defects and clinical outcome in NARP/MILS.