Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

Human Molecular Genetics

Volumn 19, Issue 9, 2010, Pages 1669-1677

  Bartesaghi, Stefano ^a,d   Betts Henderson, Joanne ^a,d   Cain, Kelvin ^a   Dinsdale, David ^a   Zhou, Xiaoshan ^b   Karlsson, Anna ^b   Salomoni, Paolo ^a,d   Nicotera, Pierluigi ^a,c  

^a UNIVERSITY OF LEICESTER   (United Kingdom)

^b KAROLINSKA INSTITUTE   (Sweden)

^c GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^d UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

MITOCHONDRIAL DNA; THYMIDINE KINASE; THYMIDINE KINASE 2; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; ATAXIA; BIOENERGY; CONTROLLED STUDY; ELECTRON TRANSPORT; ENZYME INACTIVATION; GENE NUMBER; HOMEOSTASIS; IN VIVO STUDY; KNOCKOUT MOUSE; MITOCHONDRIAL DNA DEPLETION SYNDROME; MOUSE; NERVE DEGENERATION; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEPLETION; STEADY STATE;

ANALYSIS OF VARIANCE; ANIMALS; ATAXIA; BASE SEQUENCE; BRAIN; DNA COPY NUMBER VARIATIONS; DNA, MITOCHONDRIAL; ENERGY METABOLISM; GENETIC VECTORS; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; LENTIVIRUS; MICE; MICE, KNOCKOUT; MITOCHONDRIAL DISEASES; MOLECULAR SEQUENCE DATA; MUTATION; NEURONS; THYMIDINE KINASE;

EID: 77952492113     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddq043     Document Type: Article

References (26)

1. Moraes, C.T., Shanske, S., Tritschler, H.J., Aprille, J.R., Andreetta, F., Bonilla, E., Schon, E.A. and DiMauro, S. (1991) mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am. J. Hum. Genet., 48, 492-501.
2. Alberio, S., Mineri, R., Tiranti, V. and Zeviani, M. (2007) Depletion of mtDNA: syndromes and genes. Mitochondrion, 7, 6-12.
3. McFarland, R., Taylor, R.W. and Turnbull, D.M. (2002) The neurology of mitochondrial DNA disease. Lancet Neurol., 1, 343-351.
4. Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S. and Elpeleg, O. (2001) Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat. Genet., 29, 342-344.
5. Mandel, H., Szargel, R., Labay, V., Elpeleg, O., Saada, A., Shalata, A., Anbinder, Y., Berkowitz, D., Hartman, C., Barak, M. et al. (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat. Genet., 29, 337-341.
6. Elpeleg, O., Miller, C., Hershkovitz, E., Bitner-Glindzicz, M., Bondi-Rubinstein, G., Rahman, S., Pagnamenta, A., Eshhar, S. and Saada, A. (2005) Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am. J. Hum. Genet., 76, 1081-1086.
7. Ostergaard, E., Hansen, F.J., Sorensen, N., Duno, M., Vissing, J., Larsen, P.L., Faeroe, O., Thorgrimsson, S., Wibrand, F., Christensen, E. et al. (2007) Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain, 130, 853-861.
8. Ferrari, G., Lamantea, E., Donati, A., Filosto, M., Briem, E., Carrara, F., Parini, R., Simonati, A., Santer, R. and Zeviani, M. (2005) Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain, 128, 723-731.
9. Nguyen, K.V., Ostergaard, E., Ravn, S.H., Balslev, T., Danielsen, E.R., Vardag, A., McKiernan, P.J., Gray, G. and Naviaux, R.K. (2005) POLG mutations in Alpers syndrome. Neurology, 65, 1493-1495.
10. Hakonen, A.H., Isohanni, P., Paetau, A., Herva, R., Suomalainen, A. and Lonnqvist, T. (2007) Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain, 130, 3032-3040.
11. Gotz, A., Isohanni, P., Pihko, H., Paetau, A., Herva, R., Saarenpaa-Heikkila, O., Valanne, L., Marjavaara, S. and Suomalainen, A. (2008) Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome. Brain, 131, 2841-2850.
12. Akman, H.O., Dorado, B., Lopez, L.C., Garcia-Cazorla, A., Vila, M.R., Tanabe, L.M., Dauer, W.T., Bonilla, E., Tanji, K. and Hirano, M. (2008) Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance. Hum. Mol. Genet., 17, 2433-2440.
13. Zhou, X., Solaroli, N., Bjerke, M., Stewart, J.B., Rozell, B., Johansson, M. and Karlsson, A. (2008) Progressive loss of mitochondrial DNA in thymidine kinase 2-deficient mice. Hum. Mol. Genet., 17, 2329-2335.
14. Jekabsons, M.B. and Nicholls, D.G. (2004) In situ respiration and bioenergetic status of mitochondria in primary cerebellar granule neuronal cultures exposed continuously to glutamate. J. Biol. Chem., 279, 32989-33000.
15. Wu, M., Neilson, A., Swift, A.L., Moran, R., Tamagnine, J., Parslow, D., Armistead, S., Lemire, K., Orrell, J., Teich, J. et al. (2007) Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am. J. Physiol. Cell. Physiol., 292, C125-C136.
16. Kukat, A., Kukat, C., Brocher, J., Schafer, I., Krohne, G., Trounce, I.A., Villani, G. and Seibel, P. (2008) Generation of rho0 cells utilizing a mitochondrially targeted restriction endonuclease and comparative analyses. Nucleic Acids Res., 36, e44.
17. Chen, H., McCaffery, J.M. and Chan, D.C. (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell, 130, 548-562.
18. Mandel, H., Hartman, C., Berkowitz, D., Elpeleg, O.N., Manov, I. and Iancu, T.C. (2001) The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies. Hepatology, 34, 776-784.
19. Mathews, C.K. (2006) DNA precursor metabolism and genomic stability. FASEB J., 20, 1300-1314.
20. Rylova, S.N., Mirzaee, S., Albertioni, F. and Eriksson, S. (2007) Expression of deoxynucleoside kinases and 50-nucleotidases in mouse tissues: implications for mitochondrial toxicity. Biochem. Pharmacol., 74, 169-175.
21. Oskoui, M., Davidzon, G., Pascual, J., Erazo, R., Gurgel-Giannetti, J., Krishna, S., Bonilla, E., De Vivo, D.C., Shanske, S. and DiMauro, S. (2006) Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Arch. Neurol., 63, 1122-1126.
22. Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camano, P., Marina, A., Bacman, S., Moraes, C.T., Carlo, J.R., Garcia, M. et al. (2002) Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA. Neurology, 59, 1197-1202.
23. Rocher, C., Taanman, J.W., Pierron, D., Faustin, B., Benard, G., Rossignol, R., Malgat, M., Pedespan, L. and Letellier, T. (2008) Influence of mitochondrial DNA level on cellular energy metabolism: implications for mitochondrial diseases. J. Bioenerg. Biomembr., 40, 59-67.
24. Wang, L., Limongelli, A., Vila, M.R., Carrara, F., Zeviani, M. and Eriksson, S. (2005) Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes. Mol. Genet. Metab., 84, 75-82.
25. Hatten, M.E. (1985) Neuronal regulation of astroglial morphology and proliferation in vitro. J. Cell. Biol., 100, 384-396.
26. Betts, J., Jaros, E., Perry, R.H., Schaefer, A.M., Taylor, R.W., Abdel-All, Z., Lightowlers, R.N. and Turnbull, D.M. (2006) Molecular neuropathology of MELAS: level of heteroplasmy in individual neurones and evidence of extensive vascular involvement. Neuropathol. Appl. Neurobiol., 32, 359-373.