Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice
| Autor: | Anna Karlsson, Ramon Martí, Xiaoshan Zhou, Ferran Vila-Julià, David Molina-Granada, Javier Torres-Torronteras, Yolanda Cámara, Daniel Jiménez-Heis, Cora Blázquez-Bermejo |
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| Přispěvatelé: | [Blázquez-Bermejo C, Molina-Granada D, Vila-Julià F, Torres-Torronteras J, Martí R, Cámara Y] Grup de Recerca en Patologia Neuromuscular i Mitocondrial, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Jiménez-Heis D] Grup de Recerca en Patologia Neuromuscular i Mitocondrial, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. [Zhou X, Karlsson A] Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mtdna mitochondrial DNA dCK deoxycytidine kinase Dtmp deoxythymidine monophosphate Research paper Anabolism Dck deoxycytidine kinase ADN mitocondrial Mitochondrion Deoxycytidine chemistry.chemical_compound dN deoxynucleoside 0302 clinical medicine nucleótidos y nucleósidos de ácidos nucleicos::ácidos nucleicos::ADN::ADN circular::ADN mitocondrial [COMPUESTOS QUÍMICOS Y DROGAS] Longevitat TK2 Dn deoxynucleoside Deoxynucleoside therapy Mtdna depletion TK1 thymidine kinase 1 General Medicine Deoxycytidine kinase dCtd deoxycytidine dThd deoxythymidine 030220 oncology & carcinogenesis Knockout mouse Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Thymidine Kinase [CHEMICALS AND DRUGS] medicine.medical_specialty Dnmp deoxynucleoside monophosphate Tymp thymidine phosphorylase gene Ndna nuclear DNA Encephalomyopathy Timidina CNS central nervous system General Biochemistry Genetics and Molecular Biology TK2 thymidine kinase 2 03 medical and health sciences PBS phosphate buffered saline Nucleic Acids Nucleotides and Nucleosides::Nucleic Acids::DNA::DNA Circular::DNA Mitochondrial [CHEMICALS AND DRUGS] Internal medicine medicine Dctd deoxycytidine Dntp deoxynucleoside triphosphate Thymidine phosphorylase Thymidine kinase 1 dTMP deoxythymidine monophosphate Dthd deoxythymidine Physiological Phenomena::Growth and Development::Aging::Longevity [PHENOMENA AND PROCESSES] dNMP deoxynucleoside monophosphate KO knockout Thy thymine TP thymidine phosphorylase Catabolism business.industry mtDNA depletion WT wild-type mtDNA mitochondrial DNA 030104 developmental biology Endocrinology chemistry fenómenos fisiológicos::crecimiento y desarrollo::envejecimiento::longevidad [FENÓMENOS Y PROCESOS] enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::timidina cinasa [COMPUESTOS QUÍMICOS Y DROGAS] dNTP deoxynucleoside triphosphate Dcmp deoxycytidine monophosphate nDNA nuclear DNA Thymidine business dCMP deoxycytidine monophosphate CDA cytidine deaminase |
| Zdroj: | Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona EBioMedicine Scientia |
| Popis: | Deoxycytidine; Deoxynucleoside therapy; Encephalomyopathy Desoxicitidina; Terapia basada en desoxinucleósido; Encefalomiopatía Desoxicitidina; Teràpia basada en desoxinucleòsid; Encefalomiopatia BACKGROUND: Thymidine kinase 2 (TK2) catalyses the phosphorylation of deoxythymidine (dThd) and deoxycytidine (dCtd) within mitochondria. TK2 deficiency leads to mtDNA depletion or accumulation of multiple deletions. In patients, TK2 mutations typically manifest as a rapidly progressive myopathy with infantile onset, leading to respiratory insufficiency and encephalopathy in the most severe clinical presentations. TK2-deficient mice develop the most severe form of the disease and die at average postnatal day 16. dThd+dCtd administration delayed disease progression and expanded lifespan of a knockin murine model of the disease. METHODS: We daily administered TK2 knockout mice (Tk2KO) from postnatal day 4 with equimolar doses of dThd+dCtd, dTMP+dCMP, dThd alone or dCtd alone. We monitored body weight and survival and studied different variables at 12 or 29 days of age. We determined metabolite levels in plasma and target tissues, mtDNA copy number in tissues, and the expression and activities of enzymes with a relevant role in mitochondrial dNTP anabolism or catabolism. FINDINGS: dThd+dCtd treatment extended average lifespan of Tk2KO mice from 16 to 34 days, attenuated growth retardation, and rescued mtDNA depletion in skeletal muscle and other target tissues of 12-day-old mice, except in brain. However, the treatment was ineffective in 29-day-old mice that still died prematurely. Bioavailability of dThd and dCtd markedly decreased during mouse development. Activity of enzymes catabolizing dThd and dCtd increased with age in small intestine. Conversely, the activity of the anabolic enzymes decreased in target tissues during mouse development. We also found that administration of dThd alone had the same impact on survival to that of dThd+dCtd, whereas dCtd alone had no influence on lifespan. INTERPRETATION: dThd+dCtd treatment recruits alternative cytosolic salvage pathways for dNTP synthesis, suggesting that this therapy would be of benefit for any Tk2 mutation. dThd accounts for the therapeutic effect of the combined treatment in mice. During the first weeks after birth, mice experience marked tissue-specific metabolic regulations and ontogenetic changes in dNTP metabolism-related enzymes that limit therapeutic efficacy to early developmental stages. This study was funded by grants from the Spanish Ministry of Industry, Economy and Competitiveness [grant BFU2014-52618-R and SAF2017-87506-R to YC], the Spanish Instituto de Salud Carlos III [grant PI15/00465 and grant PMP 15/00025 to RM, co-financed with ERDF], the Fundacion Inocente, Inocente [grant 2017 to YC], and AFMTelethon [grant 19,965 to YC]. JT was funded by a fellowship granted by the Generalitat de Catalunya (PERIS program, SLT002/16/00370). The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Databáze: | OpenAIRE |
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