ArticleHuman molecular genetics2011
Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.EMBO molecular medicine · 2026Article
- High tide or low tide: the transport and metabolism of mitochondrial nucleotides.The Biochemical journal · 2025Review
- Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies.Journal of neuromuscular diseases · 2022Review
- Synergistic Deoxynucleoside and Gene Therapies for Thymidine Kinase 2 Deficiency.Annals of neurology · 2021Article
- Preferent Diaphragmatic Involvement in TK2 Deficiency: An Autopsy Case Study.International journal of molecular sciences · 2021Article
- Mitochondrial DNA Depletion Syndrome and Its Associated Cardiac Disease.Frontiers in cardiovascular medicine · 2021Review
- Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency.BMC molecular and cell biology · 2020Article
- Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice.EBioMedicine · 2019Article
- Bioavailability and cytosolic kinases modulate response to deoxynucleoside therapy in TK2 deficiency.EBioMedicine · 2019Article
- A high expression of MTERF3 correlates with tumor progression and predicts poor outcomes in patients with brain glioma.International journal of clinical and experimental pathology · 2019Article
- Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.Human molecular genetics · 2017Article
- Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency.Annals of neurology · 2017Article
- Targeting nuclear thymidylate biosynthesis.Molecular aspects of medicine · 2017Review
- Article
- Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency.EMBO molecular medicine · 2014Article
- Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation.Physiological genomics · 2013Article
- Synthesis of mitochondrial DNA precursors during myogenesis, an analysis in purified C2C12 myotubes.The Journal of biological chemistry · 2013Article
- Tissue-specific oxidative stress and loss of mitochondria in CoQ-deficient Pdss2 mutant mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2013Article
- Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.PloS one · 2013Article
- Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
Deficiency of thymidine kinase 2 (TK2) is a frequent cause of isolated myopathy or encephalomyopathy in children with mitochondrial DNA (mtDNA) depletion. To determine the bases of disease onset, organ specificity and severity of TK2 deficiency, we have carefully characterized Tk2 H126N knockin mice (Tk2-/-). Although normal until postnatal day 8, Tk2-/- mice rapidly develop fatal encephalomyopathy between postnatal days 10 and 13. We have observed that wild-type Tk2 activity is constant in the second week of life, while Tk1 activity decreases significantly between postnatal days 8 and 13. The down-regulation of Tk1 activity unmasks Tk2 deficiency in Tk2-/- mice and correlates with the onset of mtDNA depletion in the brain and the heart. Resistance to pathology in Tk2 mutant organs depends on compensatory mechanisms to the reduced mtDNA level. Our analyses at postnatal day 13 have revealed that Tk2-/- heart significantly increases mitochondrial transcript levels relative to the mtDNA content. This transcriptional compensation allows the heart to maintain normal levels of mtDNA-encoded proteins. The up-regulation in mitochondrial transcripts is not due to increased expression of the master mitochondrial biogenesis regulators peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and nuclear respiratory factors 1 and 2, or to enhanced expression of the mitochondrial transcription factors A, B1 or B2. Instead, Tk2-/- heart compensates for mtDNA depletion by down-regulating the expression of the mitochondrial transcriptional terminator transcription factor 3 (MTERF3). Understanding the molecular mechanisms that allow Tk2 mutant organs to be spared may help design therapies for Tk2 deficiency.
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