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Human Molecular Genetics Advance Access published online on September 30, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn313
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The conserved translocase Tim17 prevents mitochondrial DNA loss

Michelina Iacovino1,¶,§, Caroline Granycome2,¶, Hiroshi Sembongi2, Monika Bokori-Brown2, Ronald A. Butow1, Ian J. Holt2 and Joseph M. Bateman3,*

1 Department of Molecular Biology University of Texas Southwestern Medical Center 6000 Harry Hines Blvd 75390 Dallas, Texas USA 2 MRC-Dunn Human Nutrition Unit Wellcome Trust/MRC Building Hills Road Cambridge, CB2 0XY UK 3 Wolfson Centre for Age-Related Diseases King's College London Guy's Campus London SE1 1UL UK

* Corresponding author Tel. (44) 207 8488144 Fax. (44) 207 8486816 joseph_matthew.bateman{at}kcl.ac.uk

Received July 2, 2008; Revised September 28, 2008; Accepted September 28, 2008

Maintenance of an intact mitochondrial genome is essential for oxidative phosphorylation in all eukaryotes. Depletion of mitochondrial genome copy number can have severe pathological consequences due to loss of respiratory capacity. In S. cerevisiae several bifunctional metabolic enzymes have been shown to be required for mitochondrial DNA (mtDNA) maintenance. For example, Ilv5 is required for branched chain amino acid biosynthesis and mtDNA stability. We have identified OXA1 and TIM17 as novel multicopy suppressors of mtDNA instability in ilv5 cells. In addition, over-expression of TIM17, but not OXA1, prevents the complete loss of mtDNA in cells lacking the TFAM homologue Abf2. Introduction of the disease-associated A3243G mutant mtDNA into human NT2 teratocarcinoma cells frequently causes mtDNA loss. Yet when human TIM17A is over-expressed in NT2 cybrids carrying A3243G mtDNA the proportion of cybrid clones maintaining mtDNA increases significantly. TIM17A over-expression results in long-term mtDNA stabilisation, since NT2 cybrids overexpressing TIM17A maintain mtDNA at levels similar to controls for several months. Tim17 is a conserved suppressor of mtDNA instability and is the first factor to be identified that can prevent mtDNA loss in a human cellular model of mitochondrial disease.

These authors contributed equally

§ Present address: Lillehei Heart Institute University of Minnesota 312 Church Street Minneapolis MN 55455 USA


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