The conserved translocase Tim17 prevents mitochondrial DNA loss.

TitleThe conserved translocase Tim17 prevents mitochondrial DNA loss.
Publication TypeJournal Article
Year of Publication2009
AuthorsIacovino, M, Granycome, C, Sembongi, H, Bokori-Brown, M, Butow, RA, Holt, IJ, Bateman, JM
JournalHum Mol Genet
Date Published2009 Jan 01
KeywordsDNA, Mitochondrial, Electron Transport Complex IV, Gene Expression, Humans, Membrane Transport Proteins, Mitochondrial Diseases, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins, Nuclear Proteins, Point Mutation, Repressor Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Teratocarcinoma, Tumor Cells, Cultured

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 Saccharomyces 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, overexpression 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 overexpressed in NT2 cybrids carrying A3243G mtDNA, the proportion of cybrid clones maintaining mtDNA increases significantly. TIM17A overexpression results in long-term mtDNA stabilization, 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.

Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/ddn313
PubMed ID18826960
PubMed Central IDPMC3298863
Grant ListMC_U105663140 / / Medical Research Council / United Kingdom