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.
Highlights
Mitochondria contain their own DNA, which encodes thirteen subunits of the oxidative phosphorylation (OXPHOS) complexes essential for cellular respiration and ATP production
Depletion of Mitochondria contain their own DNA (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
Does mtDNA copy number correlate with deoxynucleoside triphosphate (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
Summary
Mitochondria contain their own DNA (mtDNA), which encodes thirteen subunits of the oxidative phosphorylation (OXPHOS) complexes essential for cellular respiration and ATP production. MtDNA depletion syndromes (MDS) manifest as severe, tissue-specific diseases of early infancy [2,3,4,5] while multiple deletions typically accumulate much later in life, leading to adult-onset phenotypes in skeletal muscle and possibly in brain [6,7,8,9,10,11] These disorders are genetically heterogeneous, MDS and multiple deletions can result from mutations in the same gene [2,3,4,5,6,7,8,9,11,12,13]. Neither the function of MPV17 protein nor the mechanism leading to mtDNA perturbation is yet known
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
