MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

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 numb...

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Published inPLoS genetics Vol. 12; no. 1; p. e1005779
Main Authors Dalla Rosa, Ilaria, Cámara, Yolanda, Durigon, Romina, Moss, Chloe F, Vidoni, Sara, Akman, Gokhan, Hunt, Lilian, Johnson, Mark A, Grocott, Sarah, Wang, Liya, Thorburn, David R, Hirano, Michio, Poulton, Joanna, Taylor, Robert W, Elgar, Greg, Martí, Ramon, Voshol, Peter, Holt, Ian J, Spinazzola, Antonella
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 01.01.2016
Public Library of Science (PLoS)
Subjects
Animals
Brain research
Cell and Molecular Biology
Cell- och molekylärbiologi
Deoxyguanine Nucleotides - genetics
Deoxyribonucleic acid
Disease
DNA
DNA replication
DNA Replication - genetics
DNA sequencing
DNA, Mitochondrial - genetics
Enzymes
Female
Fibroblasts
Fibroblasts - metabolism
Gene Expression Regulation
Genes
Homeostasis
Humans
Kinases
Liver
Medical research
Membrane Proteins - deficiency
Membrane Proteins - genetics
Metabolism
Mice
Mitochondria
Mitochondria, Liver - genetics
Mitochondria, Liver - metabolism
Mitochondrial diseases
Mitochondrial DNA
Mutation
Nucleotide sequencing
Observations
Physiological aspects
Proteins
Ribonucleotide reductase
Scholarships & fellowships
Signal Transduction
Thymine Nucleotides - genetics
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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.
AbstractList 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.
  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.
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.sup.-/-] 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.sup.-/-] 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.
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. Mitochondrial DNA depletion syndrome (MDS) is a genetically heterogeneous condition characterized by a decrease of mitochondrial DNA (mtDNA) copy number and decreased activities of respiratory chain enzymes. Depletion of mtDNA has been associated with mutations in several genes, which encode either proteins directly involved in mtDNA replication or factors regulating the homeostasis of the mitochondrial deoxynucleotide pool. However, for some genes the mechanism linking mutations and mtDNA depletion is not known. One such gene is MPV17 , whose loss-of-function causes mtDNA abnormalities in human, mouse and yeast. Here we show that MPV17 dysfunction leads to a shortage of the precursors for DNA synthesis in the mitochondria, slowing DNA replication in the organelle. Not only does mtDNA copy number correlate with dNTP pool size in both mouse tissues and human cells, deoxynucleoside supplementation of the growth medium prevents depletion and restores mtDNA copy number in quiescent MPV17-deficient cells. Hence, our study links MPV17 deficiency, insufficiency of mitochondrial dNTPs, and slow replication in mitochondria to depletion of mtDNA manifesting in the human disease, and places MPV17-related disease firmly in the category of mtDNA disorders caused by deoxynucleotide perturbation. The prevention and reversal of mtDNA loss in MPV17 patient-derived cells identifies potential therapeutic strategy for a currently untreatable disease.
Audience Academic
Author Voshol, Peter
Akman, Gokhan
Grocott, Sarah
Johnson, Mark A
Thorburn, David R
Durigon, Romina
Spinazzola, Antonella
Elgar, Greg
Taylor, Robert W
Vidoni, Sara
Holt, Ian J
Dalla Rosa, Ilaria
Poulton, Joanna
Martí, Ramon
Cámara, Yolanda
Moss, Chloe F
Hunt, Lilian
Wang, Liya
Hirano, Michio
AuthorAffiliation 3 Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
10 Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
4 MRC Mitochondrial Biology Unit, Wellcome Trust-MRC Building, Cambridge, United Kingdom
Max Planck Institute for Biology of Ageing, GERMANY
8 Department of Neurology, Columbia University Medical Center, New York, New York, United States of America
9 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, The Medical School, Newcastle upon Tyne, United Kingdom
7 Murdoch Childrens Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Flemington Road, Parkville, Victoria, Australia
1 MRC Mill Hill Laboratory, London, United Kingdom
5 Mitochondrial Genetics Group, Nuffield Department of Obstetrics and Gynaecology, Women's Centre, The John Radcliffe Hospital, Oxford, United Kingdom
6 Department of Anatomy, Physiology and Bioche
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https://res.slu.se/id/publ/79691$$DView record from Swedish Publication Index
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ContentType Journal Article
Copyright COPYRIGHT 2016 Public Library of Science
2016 Dalla Rosa et al 2016 Dalla Rosa et al
2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Dalla Rosa I, Cámara Y, Durigon R, Moss CF, Vidoni S, Akman G, et al. (2016) MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. PLoS Genet 12(1): e1005779. doi:10.1371/journal.pgen.1005779
Copyright_xml – notice: COPYRIGHT 2016 Public Library of Science
– notice: 2016 Dalla Rosa et al 2016 Dalla Rosa et al
– notice: 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Dalla Rosa I, Cámara Y, Durigon R, Moss CF, Vidoni S, Akman G, et al. (2016) MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. PLoS Genet 12(1): e1005779. doi:10.1371/journal.pgen.1005779
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DocumentTitleAlternate MPV17 Deficiency Causes dNTP Insufficiency in Mitochondria
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Conceived and designed the experiments: AS IDR IJH. Performed the experiments: AS IDR YC RD CFM LH SV GA MAJ. Analyzed the data: AS IDR YC LH GE RM IJH. Contributed reagents/materials/analysis tools: DRT RWT MH JP RM SG PV LW. Wrote the paper: AS IJH.
The authors have declared that no competing interests exist.
OpenAccessLink https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711891/
PMID 26760297
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Snippet MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of...
  MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations...
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StartPage e1005779
SubjectTerms Animals
Brain research
Cell and Molecular Biology
Cell- och molekylärbiologi
Deoxyguanine Nucleotides - genetics
Deoxyribonucleic acid
Disease
DNA
DNA replication
DNA Replication - genetics
DNA sequencing
DNA, Mitochondrial - genetics
Enzymes
Female
Fibroblasts
Fibroblasts - metabolism
Gene Expression Regulation
Genes
Homeostasis
Humans
Kinases
Liver
Medical research
Membrane Proteins - deficiency
Membrane Proteins - genetics
Metabolism
Mice
Mitochondria
Mitochondria, Liver - genetics
Mitochondria, Liver - metabolism
Mitochondrial diseases
Mitochondrial DNA
Mutation
Nucleotide sequencing
Observations
Physiological aspects
Proteins
Ribonucleotide reductase
Scholarships & fellowships
Signal Transduction
Thymine Nucleotides - genetics
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Title MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria
URI https://www.ncbi.nlm.nih.gov/pubmed/26760297
https://search.proquest.com/docview/1760868752
https://pubmed.ncbi.nlm.nih.gov/PMC4711891
https://res.slu.se/id/publ/79691
https://doaj.org/article/fd0c8fb28a5f40f98a92dee74e9682c6
http://dx.doi.org/10.1371/journal.pgen.1005779
Volume 12
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