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The role of the Mpv17 protein mutations of which cause mitochondrial DNA depletion syndrome (MDDS): lessons from homologs in different species

  • Abstract Mitochondrial DNA depletion syndromes (MDDS) are severe pediatric diseases with diverse clinical manifestations. Gene mutations that underlie MDDS have been associated with alterations in the mitochondrial DNA (mtDNA) replication machinery or in mitochondrial deoxyribonucleoside triphosphate pools. However, the nuclear gene MPV17, whose mutated forms are associated with hepatocerebral MDDS in humans, plays a so-far unknown role in mtDNA maintenance. A high degree of conservation has been determined between MPV17 and its mouse (Mpv17), zebrafish (tra) and yeast (SYM1) homologs, respectively, whereby mutants in these cause very different phenotypes. While dysfunction in this gene in humans causes fatal liver disease, kidney pathology is induced in mice. Moreover, in zebrafish inactivation of the Mpv17 homolog was detected as a viable dyscolouration mutant. Knock out of the yeast ortholog results in a temperature-sensitive metabolic growth phenotype. Detailed analyses on common denominators between these different phenotypes strengthen the hypothesis that the Mpv17 protein forms a channel in the inner mitochondrial membrane, allowing small molecules - in vertebrates probably nucleotides, and in yeast probably intermediates of the tricarboxylic acid cycle - to pass. Moreover, a function modifying the pathologic manifestations of MPV17-related disease in mice has been identified. This signaling pathway remarkably involves the non-mitochondrial catalytic subunit of DNA-dependent protein kinase (PRKDC), important in double-strand break repair resistance against reactive oxygen-induced genotoxic stress.

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Metadaten
Document Type:Article
Language:English
Parent Title (English):Biol Chem. (Biological Chemistry)
Volume:396
Issue:1
First Page:13
Last Page:25
ISSN:1437-4315
DOI:https://doi.org/10.1515/hsz-2014-0198
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=25205723
Publisher:De Gruyter
Place of publication:Berlin
Date of first publication:2014/09/02
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IfGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 576 Genetik und Evolution
Entry in this database:2015/04/02