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Acta Myol. 2009 July; 28(1): 32.
PMCID: PMC2859633

H-1. Disorders of mitochondrial DNA maintenance and integrity

Instability of mtDNA, consisting of deletions, depletion, or both, is a major cause of mitochondrial dysfunction and disease. Twenty years have elapsed since the discovery of single mtDNA deletions in sporadic Kearns-Sayre syndrome or its milder variant, Progressive External Ophthalmoplegia (PEO).

Shortly thereafter, the accumulation of multiple mtDNA-deleted species was observed in autosomal dominant PEO. Mendelian inheritance of deletions sounded weird at first, as it is known that mtDNA is transmitted maternally, but was then explained as the consequence of a dominant mutation in a nuclear gene affecting the structural integrity of mtDNA. This hypothesis led to the discovery of five disease genes: ANT1, Twinkle, POLG1/ 2 and OPA1. On the other hand, mitochondrial DNA depletion syndromes (MDS) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in Thymidine Kinase 2 and p53-induced Ribonucleotide Reductase B subunit; the second with mutations in succinate synthase A and B; the third with recessive mutations in Twinkle, POLG1, deoxyguanosine kinase and MPV17. Mpv17, a 20 kDa mitochondrial membrane protein of unknown function. In humans as well as in knockout (ko) mice, absence of Mpv17 is associated with profound depletion of liver mtDNA.

Patients die of acute hypoglycemic crises or progressive hepato-cerebral failure, but ko mice have hardly any hepatic alteration whereas they develop massive proteinuria due to specific mtdNA depletionin the renal glomeruli. Taken together, these results suggest for Mpv17 a dual role, on intermediate metabolism and mtDNA maintenance. Yeast strains lacking SYM1, the ortholog of Mpv17, display a metabolic phenotype characterized by thermosensitive failure of aerobic growth and propensity to form - petite clonies. Further investigation suggests a role for Mpv17 in the handling of Krebs-cycle intermediates, which may partly explain both the metabolic and the molecular features of the human syndrome. The models discussed here offer interesting clues for the interpretation of clinical features, but they also display unexpected features, raising further questions on the role of targeted genes in normal and disease conditions.

Articles from Acta Myologica are provided here courtesy of Pacini Editore