ReviewGene to screenFeeding the deoxyribonucleoside salvage pathway to rescue mitochondrial DNA
Section snippets
A particular group of MDDSs: defects in dNTP homeostasis
As was mentioned above, many nuclear genes that have been related to MDDS up to now encode proteins directly involved in regulation of the dNTP pool homeostasis. Both nuclear DNA and mtDNA depend on balanced pools of dNTPs to ensure fidelity of the replication and repair processes [12]. The size and composition of these pools affect genetic stability, and their homeostasis is crucial for maintenance of both genomes.
Mammalian cells obtain the precursors for DNA synthesis and repair from two
Limited availability of dNTPs as a common trait leading to mtDNA depletion
Although it is generally assumed that imbalances in the mitochondrial dNTP pool interfere with normal replication and repair processes, the precise mechanisms involved are largely unknown. When the activity of nucleoside kinases in the mitochondrial salvage pathway is insufficient, as is the case of TK2 or dGK deficiencies, or when the de novo synthesis pathway is compromised owing to mutations in the gene encoding p53R2, the resulting decrease in the corresponding dNTP products predictably
Limitations of present models for MDDS study
One important drawback when testing potential therapeutic approaches for MDDSs is the limited availability of in vitro and in vivo models that accurately reproduce the disease phenotypes. Actually, most patient-derived cells harboring mutations in mitochondrial dNTP metabolism-related enzymes do not develop mtDNA depletion in vitro, with dGK-deficient cells being an exception [28]. One puzzling feature of MDDSs is that they manifest in a tissue-specific manner although expression of the mutated
First idea: bypass the affected salvage reaction by supplying the deficient product
The first attempts to correct mitochondrial dNTP pool imbalances were addressed to deficiencies in mitochondrial nucleoside kinases from the salvage pathway. dGK is the first and rate-limiting step in the salvage of purine deoxyribonucleosides within mitochondria. It phosphorylates deoxyadenosine (dAdo) and deoxyguanosine (dGuo) to the corresponding monophosphates (dAMP and dGMP), which will subsequently undergo consecutive phosphorylations to dATP and dGTP. The addition of both defective
Feeding the deoxyribonucleoside salvage pathways as a way to counteract mtDNA depletion due to defects in dNTP metabolism
Growing evidence indicates that administration of deoxyribonucleosides as precursors of dNTPs through the nucleoside salvage pathway may be an efficient alternative to direct supply of the missing product of the dysfunctional enzyme. As was mentioned above, cytosol and mitochondria are separate compartments that actively communicate. The exchange of deoxyribonucleosides and their nucleotides between these two compartments has been well documented [16], but the specific carriers responsible for
Inhibition of deoxyribonucleoside catabolism as an alternative or complementary approach
Deoxyribonucleoside availability for cells depends on the balance between their generation (i.e. de novo synthesis and dietary incorporation) and their consumption by DNA replication and catabolic enzymes. As precursors for dNTP formation, deoxyribonucleosides are subjected to tight control by activity of catabolic enzymes that limit salvage by deoxyribonucleoside kinases [16]. Many nucleoside analogs used for chemotherapy are in fact substrates of the same degrading enzymes. This catabolic
Therapeutic perspectives on increasing deoxyribonucleoside availability for the treatment of MDDSs
Genetic and clinical heterogeneity are hallmarks of MDDSs and, together with the low frequency of these conditions, represent the main difficulties when designing novel strategies for their treatment. These characteristics make the diagnosis, prognosis, and treatment of MDDSs a challenging task. Although our understanding of the pathomechanisms underlying mitochondrial deficiencies has dramatically increased in the past years thanks to studies in animal and in vitro models 4, 5, 24, we are
Acknowledgements
J.T. was funded by the United Mitochondrial Disease Foundation (UMDF) with a postdoctoral grant (12-029) and R.M. was funded by the Instituto de Salud Carlos IIII (grant PI12/00322). We thank Celine Cavallo for English Language assistance.
References (68)
- et al.
Disorders of nuclear-mitochondrial intergenomic signaling
Gene
(2005) - et al.
Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options
Neurotherapeutics
(2013) - et al.
Mitochondrial DNA depletion syndromes – many genes, common mechanisms
Neuromuscul. Disord.
(2010) Mutations in DNA2 link progressive myopathy to mitochondrial DNA instability
Am. J. Hum. Genet.
(2013)A UV-responsive internal ribosome entry site enhances serine hydroxymethyltransferase 1 expression for DNA damage repair
J. Biol. Chem.
(2009)Regulation by degradation, a cellular defense against deoxyribonucleotide pool imbalances
Mutat. Res.
(2010)Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs
J. Biol. Chem.
(2004)The pyrimidine nucleotide carrier PNC1 and mitochondrial trafficking of thymidine phosphates in cultured human cells
Exp. Cell Res.
(2012)- et al.
Mouse models of mtDNA replication diseases
Methods
(2010) Thymidine and deoxyuridine accumulate in tissues of patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
FEBS Lett.
(2007)
Mitochondrial DNA depletion and thymidine phosphate pool dynamics in a cellular model of mitochondrial neurogastrointestinal encephalomyopathy
J. Biol. Chem.
Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase
J. Biol. Chem.
Recessive deoxyguanosine kinase deficiency causes juvenile onset mitochondrial myopathy
Mol. Genet. Metab.
A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions
Am. J. Hum. Genet.
MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle
Neuromuscul. Disord.
POLG mutations cause decreased mitochondrial DNA repopulation rates following induced depletion in human fibroblasts
Biochim. Biophys. Acta
Synthesis of mitochondrial DNA precursors during myogenesis, an analysis in purified C2C12 myotubes
J. Biol. Chem.
Transgene expression of Drosophila melanogaster nucleoside kinase reverses mitochondrial thymidine kinase 2 deficiency
J. Biol. Chem.
Mitochondrial deoxyribonucleotide pools in deoxyguanosine kinase deficiency
Mol. Genet. Metab.
Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine
Blood
Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia
Blood
Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia
Am. J. Hum. Genet.
Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion
Am. J. Hum. Genet.
Mitochondrial respiratory-chain diseases
N. Engl. J. Med.
Defects in mitochondrial DNA replication and human disease
Crit. Rev. Biochem. Mol. Biol.
Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease
Nat. Genet.
Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy
Nat. Genet.
The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA
Nat. Genet.
Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions
Brain
Thymidine kinase 2 mutations in autosomal recessive progressive external ophthalmoplegia with multiple mitochondrial DNA deletions
Hum. Mol. Genet.
DNA precursor metabolism and genomic stability
FASEB J.
SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis
PLoS ONE
Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria
Proc. Natl. Acad. Sci. U. S. A.
HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase
Nature
Cited by (12)
Strategies for treating mitochondrial disorders: An update
2014, Molecular Genetics and MetabolismCitation Excerpt :Nuclear gene mutations causing an imbalance of mitochondrial nucleotide pools (dNTP) in mitochondria are involved in this class of MD and nucleotide supplementation has been hypothesized to be potentially beneficial in these conditions [120]. In several MDS cell models, deoxyribonucleosides (dNs) or their corresponding deoxyribonucleoside monophosphates (dNMPs) are reported to be effective in normalizing the mitochondrial nucleotide pool and in restoring the mtDNA copy number [121–126]. Similar effects can be obtained by specific inhibition of dN catabolism, which could stabilize coadministered dNs, induce a sufficient increase in their endogenous concentrations, or both [127].
Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice
2023, International Journal of ObesityDeoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice
2022, Research SquareStimulating Mitochondrial Biogenesis with Deoxyribonucleosides Increases Functional Capacity in ECHS1-Deficient Cells
2022, International Journal of Molecular SciencesInborn Errors of Nucleoside Transporter (NT)-Encoding Genes (SLC28 and SLC29)
2022, International Journal of Molecular SciencesCharacterization of microbial communities and predicted metabolic pathways in the uterus of healthy mares
2022, Open Veterinary Journal
- 4
These authors contributed equally to this work.
- 5
Present address: Child and Adolescent Psychiatry Department, Instituto de Investigación Sanitaria Gregorio Marañón, IiSGM, Hospital General Universitario Gregorio Marañón, CIBERSAM, Madrid, Spain.