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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Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome.
Front Cell Dev Biol
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Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom.
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- Mitochondrial DNA depletion syndrome (MDS) is a condition where patients struggle to make enough energy because they lack proper mitochondrial DNA (mtDNA).
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- In experiments, one specific combination of nucleosides called ATGC worked really well at helping increase mtDNA in certain cells after being depleted, although higher doses caused some toxic effects.
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Neurology Department, Neuromuscular Disorders Unit, Hospital 12 de Octubre, Madrid 28041, Spain; Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Madrid 28029, Spain; Mitochondrial and Neuromuscular Research Group '12 de Octubre', Hospital Research Institute (imas12), Madrid 28041, Spain. Electronic address:
Objectives: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive mitochondrial disorder. It manifests as a continuous clinical spectrum, from fatal infantile mitochondrial DNA depletion syndromes to adult-onset mitochondrial myopathies characterized by ophthalmoplegia-plus phenotypes with early respiratory involvement. Treatment with pyrimidine nucleosides has recently shown striking effects on survival and motor outcomes in the more severe infantile-onset clinical forms.
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Objectives: Thymidine kinase 2 deficiency (TK2d) is a rare autosomal recessive disorder that stems from a perturbation of the mitochondrial DNA maintenance. Nucleoside treatment has recently shown promise as a disease-modifying therapy. TK2d was initially associated with rapidly progressive fatal myopathy in children featuring mitochondrial DNA depletion.
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November 2023
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Deficiency in thymidine kinase 2 (TK2) causes mitochondrial DNA depletion. Liver mitochondria are severely affected in Tk2 complete knockout models and have been suggested to play a role in the pathogenesis of the Tk2 knockout phenotype, characterized by loss of hypodermal fat tissue, growth retardation and reduced life span. Here we report a liver specific Tk2 knockout (KO) model to further study mechanisms contributing to the phenotypic changes associated with Tk2 deficiency.
View Article and Find Full Text PDFEfficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.
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From the Massachusetts General Hospital (A.K.), Harvard Medical School Boston; Neuromuscular Unit (E.B.), Bambino Gesù Ospedale Pediatrico, IRCCS, Rome; IRCCS Istituto delle Scienze Neurologiche di Bologna (V.C.), Programma di Neurogenetica; Department of Biomedical and Neuromotor Sciences (V.C.), University of Bologna, Italy; Rebecca D. Considine Research Institute (B.H.C.), Akron Children's Hospital, OH; Stanford University School of Medicine (G.M.E.), CA; Mitochondrial Medicine Frontier Program (M.J.F., A.G.), Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine; Royal Victoria Infirmary (G.S.G.), Newcastle upon Tyne, United Kingdom; University of California (R.H.), San Diego, La Jolla; Columbia University Irving Medical Center (M.H.), New York; Friedrich-Baur-Institute (T.K.), Department of Neurology, LMU Hospital, Ludwig Maximilian University of Munich; German Center for Neurodegenerative Diseases (DZNE); Munich Cluster for Systems Neurology (SyNergy), Germany; Department of Pediatrics (M.K.K.), University of Texas McGovern Medical School, Houston; Department of Neurology, Neuromuscular Diseases Section (C.K.), University Hospital of Bonn, Germany; Fondazione IRCCS Istituto Neurologico Carlo Besta (C.L.), Milano, Italy; Vancouver General Hospital (A.L.), British Columbia, Canada; University of Utah (N.L.), Salt Lake City; Institute of Genomic Medicine and Rare Disorders (M.J.M.), Semmelweis University, Budapest, Hungary; Cleveland Clinic Neurological Institute (S.P.), OH; Rare Disease Research (H.P.), Atlanta, GA; Department of Neuromuscular Diseases (R.D.S.P.), UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, United Kingdom; Seattle Children's Hospital (R.S.), WA; Baylor College of Medicine (F.S.), Houston, TX; Texas Children's Hospital (F.S.); Joint BCM-CUHK Center of Medical Genetics (F.S.), Hong Kong SAR; Fondazione Policlinico Universitario A. Gemelli and Istituto di Neurologia (S.S.), Università Cattolica del Sacro Cuore, Rome, Italy; McMaster University Medical Center (M.T.), Hamilton, Ontario, Canada; Neurology and Neuromuscular Unit (A.T.), Department of Clinical and Experimental Medicine, University of Messina, Italy; University of Colorado and Children's Hospital Colorado (J.L.K.V.H.), Aurora; Copenhagen Neuromuscular Center (John Vissing), Rigshospitalet University of Copenhagen, Denmark; Children's Hospital of Pittsburgh (Jerry Vockley), University of Pittsburgh School of Medicine, PA; Jupiter Point Pharma Consulting (J.S.F.), LLC; Stealth BioTherapeutics (D.A.B.)Write On Time Medical Communications (J.A.S.), LLC; and Department of Clinical and Experimental Medicine (M.M.), Neurological Institute, University of Pisa, Italy.
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