10779/crick.12657251.v1
Ilaria Dalla Rosa
Ilaria Dalla
Rosa
Yolanda Cámara
Yolanda
Cámara
Romina Durigon
Romina
Durigon
Chloe F Moss
Chloe F
Moss
Sara Vidoni
Sara
Vidoni
Gokhan Akman
Gokhan
Akman
Lilian Hunt
Lilian
Hunt
Mark A Johnson
Mark A
Johnson
Sarah Grocott
Sarah
Grocott
Liya Wang
Liya
Wang
David R Thorburn
David R
Thorburn
Michio Hirano
Michio
Hirano
Joanna Poulton
Joanna
Poulton
Robert W Taylor
Robert W
Taylor
Greg Elgar
Greg
Elgar
Ramon Marti
Ramon
Marti
Peter Voshol
Peter
Voshol
Ian J Holt
Ian J
Holt
Antonella Spinazzola
Antonella
Spinazzola
MPV17 loss causes deoxynucleotide insufficiency and slow DNA replication in mitochondria
The Francis Crick Institute
2020
Animals
DNA Replication
DNA, Mitochondrial
Deoxyguanine Nucleotides
Female
Fibroblasts
Gene Expression Regulation
Humans
Membrane Proteins
Mice
Mitochondria, Liver
Signal Transduction
Thymine Nucleotides
Elgar FC001075
0604 Genetics
Developmental Biology
2020-07-17 16:28:10
Journal contribution
https://crick.figshare.com/articles/journal_contribution/MPV17_loss_causes_deoxynucleotide_insufficiency_and_slow_DNA_replication_in_mitochondria/12657251
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.