Toggle Main Menu Toggle Search

Open Access padlockePrints

MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

Lookup NU author(s): Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17(-/-) liver slows the DNA replication in the organelle, as evidenced by the elevated level of replication intermediates. Quiescent fibroblasts of MPV17-mutant patients recapitulate key features of the primary affected tissue of the Mpv17(-/-) mice, displaying virtual absence of the protein, decreased dNTP levels and mitochondrial DNA depletion. Notably, the mitochondrial DNA loss in the patients' quiescent fibroblasts was prevented and rescued by deoxynucleoside supplementation. Thus, our study establishes dNTP insufficiency in the mitochondria as the cause of mitochondrial DNA depletion in MPV17 deficiency, and identifies deoxynucleoside supplementation as a potential therapeutic strategy for MPV17-related disease. Moreover, changes in the expression of factors involved in mitochondrial deoxynucleotide homeostasis indicate a remodeling of nucleotide metabolism in MPV17 disease models, which suggests mitochondria lacking functional MPV17 have a restricted purine mitochondrial salvage pathway.

Publication metadata

Author(s): Rosa ID, Camara Y, Durigon R, Moss CF, Vidoni S, Akman G, Hunt L, Johnson MA, Grocott S, Wang LY, Thorburn DR, Hirano M, Poulton J, Taylor RW, Elgar G, Marti R, Voshol P, Holt IJ, Spinazzola A

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2016

Volume: 12

Issue: 1

Online publication date: 13/01/2016

Acceptance date: 08/12/2015

Date deposited: 19/10/2016

ISSN (electronic): 1553-7404

Publisher: Public Library of Science


DOI: 10.1371/journal.pgen.1005779


Altmetrics provided by Altmetric


Funder referenceFunder name
Australian National Health and Medical Research Council
Muscular Dystrophy Association-Telethon (AFM Telethon)
UK NHS Highly Specialized Rare Mitochondrial Disorders of Adults and Children Service
096919/Z/11/ZWellcome Trust
MC_PC_13029Medical Research Council
PI12/00322Spanish Instituto de Salud Carlos III
PIEF-GA-2009-255578European Union Marie Curie Fellowship