title: MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria.
abstract: 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.
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dalla Rosa
authors.affiliation: Laboratory of Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Catalonia.|Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Cámara
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Romina
authors.initials: R
authors.lastname: Durigon
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Chloe F
authors.initials: CF
authors.lastname: Moss
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust-MRC Building, Cambridge, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Vidoni
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Gokhan
authors.initials: G
authors.lastname: Akman
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Lilian
authors.initials: L
authors.lastname: Hunt
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust-MRC Building, Cambridge, United Kingdom.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Johnson
authors.affiliation: Mitochondrial Genetics Group, Nuffield Department of Obstetrics and Gynaecology, Women's Centre, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Grocott
authors.affiliation: Department of Anatomy, Physiology and Biochemistry, The Swedish University of Agricultural Sciences, Biomedical Center, Uppsala, Sweden.
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.affiliation: Murdoch Childrens Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Flemington Road, Parkville, Victoria, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.affiliation: Mitochondrial Genetics Group, Nuffield Department of Obstetrics and Gynaecology, Women's Centre, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Poulton
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Greg
authors.initials: G
authors.lastname: Elgar
authors.affiliation: Laboratory of Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Catalonia.|Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Martí
authors.affiliation: Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Voshol
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Holt
authors.affiliation: MRC Mill Hill Laboratory, London, United Kingdom.
authors.forename: Antonella
authors.initials: A
authors.lastname: Spinazzola
mesh_terms: D000818:Animals; D004261:DNA Replication / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D003848:Deoxyguanine Nucleotides / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008930:Mitochondria, Liver / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013942:Thymine Nucleotides / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D003848:Deoxyguanine Nucleotides; D008565:Membrane Proteins; C065292:Mpv17 protein, mouse; D013942:Thymine Nucleotides; C029603:deoxyguanosine triphosphate; C024157:thymidine 5'-triphosphate