Unravelling the function of MPV17

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) include a group of mitochondrial diseases characterized by mtDNA instability. In 2006, we found pathogenic mutations in a gene called Mpv17 in patients with a rather specific hepato-cerebral form of MDS. The patients surviving acute liver failure, dominated by hypoglycemic crises and cirrhotic evolution of the liver parenchyma, develop progressive ataxia and neurological impairment. Depletion of mtDNA in liver and brain (neuro-hepatopathy) is indeed the molecular and clinical hallmark of mutations in Mpv17, a protein of the inner membrane of mitochondria, the function of which is presently unknown. The aim of this project is to understand whether, as hypothesized from previous work, Mpv17 is part or forms a channel through which metabolites that must be characterized are translocated in/out the mitochondria. To achieve these aims, we want to overexpress the protein in suitable cells and look at it in native conditions through a special high resolution electron-microscopy based visualization (cryo-EM) that allows protein structures to be detected. A second objective is to understand which metabolites are allowed to pass through the Mpv17 channel, if this structure will be confirmed, and the third objective will be to understand why the block of this transport can determine the loss of mitochondrial DNA in liver and brain. This information will let us understand the mechanism underlying one of the most common and still unresolved syndromes characterized by hepato-cerebral mtDNA depletion in children.