The zebrafish orthologue of the human hepatocerebral disease gene MPV17 plays pleiotropic roles in mitochondria.

Mitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction of mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17 , a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. Zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17. In our work, we have characterized the mitochondrial phenotype of mpv17 -/- larvae and found early and severe ultrastructural alterations in liver mitochondria as well as a significant impairment of the respiratory chain leading to activation of the mitochondrial quality control. Our results provide evidences for zebrafish Mpv17 being essential for maintaining mitochondrial structure and functionality while its effect on mtDNA copy number seems to be subordinate. Considering that a role in nucleotides availability had already been postulated for MPV17, that embryos blocked in pyrimidine synthesis do phenocopy mpv17 -/- KO and that mpv17 -/- KO have an impaired Dihydroorotate dehydrogenase activity, we provided mpv17 mutants with the pyrimidine precursor orotic acid (OA). The treatment with OA, an easily available food supplement, significantly increased both iridophores number and mtDNA content of mpv17 -/- mutants, thus linking the loss of Mpv17 to pyrimidine de novo synthesis and opening a new simple therapeutic approach for MPV17 -related MDS.