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MITOCHONDRIAL DNA MAINTENANCEMITOCHONDRIAL DNA MAINTENANCE Human mitochondrial DNA (mtDNA), ‘our other genome’, was fully sequenced in 1981 and represents a separate genome present from several hundreds to thousands of copies per cell. It encodes thirteen protein subunits of the respiratory chain and ATP synthase, plus the 2 rRNAs and 22 tRNAs required for their synthesis on mitochondrial ribosomes. The 13 mtDNA encoded proteins are subunits of four of the five oxidative phosphorylation complexes and therefore indispensible for cellular energy production. Maintenance of an intact mitochondrial genome is therefore essential for viability and for the completion of development. In mammals, mtDNA is exclusively inherited via the maternal line, thus mtDNA disease mutations are solely transmitted from mother to offspring. MtDNA disease mutations can be classified as maternally inherited or ‘spontaneous’ germline mutations, but can also be the consequence of mutations in nuclear genes coding for proteins involved in mtDNA maintenance. In the latter case, the disease is often restricted to some tissues and does not normally affect the female germline. Inheritance is thus Mendelian and most nuclear ‘mtDNA disease’ genes have been identified using the rationale of Mendelian disease genetics. MtDNA is organized in foci, termed nucleoids, as small assemblies containing 2-10 mtDNA copies and various proteins that are poorly conserved in evolution. Despite a renewed interest in mtDNA due to its involvement in human disease and ageing, there are still many fundamental questions surrounding faithful copying (replication), repair and inheritance of mtDNA in humans. My laboratory aims to address these questions in part via the identification and characterization of those mitochondrial proteins that are part of nucleoids or play a role in their biology, that is to say we concentrate on the machineries in the cell and the mitochondrion that are involved in the maintenance of mtDNA in all its aspects. Ultimately, the aim is to not only understand the very basic molecular biology of for example mtDNA replication and repair and individual nucleoid proteins but to also understand mtDNA maintenance at the cell biological and organismal level. This will not only provide fundamental insight in one of the least understood processes in the cell, it will also provide a framework to understand and possibly treat mtDNA disease.
Members Pohjoismäki, J.L.O., Holmes, J.B., Wood, S.R., Yang, M.-Y., Yasukawa, T., Reyes, A., Bailey, L.J., Cluett, T.J., Goffart, S., Willcox, S., Rigby, R.E., Jackson, A.P., Spelbrink, J.N., Griffith, J.D., Crouch, R.J., Jacobs, H.T. and Holt, I.J. Mammalian Mitochondrial DNA Replication Intermediates Are Essentially Duplex but Contain Extensive Tracts of RNA/DNA Hybrid. Journal of Molecular Biology, 397, 1144-1155. Spelbrink J.N. (2010) Functional organization of mammalian mitochondrial DNA in nucleoids: history, recent developments, and future challenges. IUBMB Life 62, 19-32. Duxin, J.P., Dao, B., Martinsson, P., Rajala, N., Guittat, L., Campbell, J.L., Spelbrink, J.N. and Stewart, S.A. (2009) Human Dna2 is a Nuclear and Mitochondrial
Cooper, H.M., Huang, J-Y., Verdin, E. and Spelbrink, J.N. (2009) A new splice variant of the mouse SIRT3 gene encodes the mitochondrial precursor protein. PLoS
Goffart, S., Cooper, H.M., Tyynismaa, H., Wanrooij, S., Suomalainen, A. and Spelbrink, J.N. (2009) Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet 18, 328-340. Hakonen, A. H., Goffart, S., Marjavaara, S., Paetau, A., Cooper, H., Mattila, K., Lampinen, M., Sajantila, A., Lonnqvist, T., Spelbrink, J. N., and Suomalainen, A. (2008) Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Hum Mol Genet 17, 3822-3835. Krishnan, K. J., Reeve, A. K., Samuels, D. C., Chinnery, P. F., Blackwood, J. K., Taylor, R. W., Wanrooij, S., Spelbrink, J. N., Lightowlers, R. N., and Turnbull, D. M. (2008) What causes mitochondrial
Cooper, H. M. and Spelbrink, J.N. (2008) The human Sirt3 protein deacetylase is exclusively mitochondrial. Biochemical J, 411, 279-85. Sarzi, E., Goffart, S., Serre, V., Chretien, D., Slama, A., Munnich, A., Spelbrink, J. N., and Rotig, A. (2007) Twinkle helicase (
Wanrooij, S., Goffart, S., Pohjoismaki, J. L., Yasukawa, T., and Spelbrink, J. N. (2007) Expression of catalytic mutants of the mtDNA helicase Twinkle and polymerase POLG causes distinct replication stalling phenotypes. Nucleic Acids Res 35, 3238-51. Holt, I. J., He, J., Mao, C. C., Boyd-Kirkup, J. D., Martinsson, P., Sembongi, H., Reyes, A., and Spelbrink, J. N. (2007) Mammalian mitochondrial nucleoids: Organizing an independently minded genome. Mitochondrion 7, 311-21. He, J., Mao, C.C., Reyes, A., Sembongi, H., Di Re, M., Granycome, C., Clippingdale, A.B., Fearnley, I.M., Harbour, M., Robinson, A.J., Reichelt, S., Spelbrink, J.N., Walker, J.E. and Holt, I.J. (2007) The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization. J Cell Biol, 176, 141-146. Tyynismaa, H., Mjosund, K. P., Wanrooij, S., Lappalainen, I., Ylikallio, E., Jalanko, A., Spelbrink, J.N., Paetau, A., and Suomalainen, A. (2005) Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc Natl Acad Sci U S A 102, 17687-92. Wanrooij, S., Luoma, P., van Goethem, G., van Broeckhoven, C., Suomalainen, A. and Spelbrink, J.N. (2004) Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucl Acids Res 32, 3053-3064. Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E., Bohlooly-Y, M., Gidlof, S., Oldfors, A., Wibom, R. et al. (2004) Premature ageing in mice expressing defective mitochondrial
Garrido N., Griparic, L., Jokitalo E., Wartiovaara J., Van der Bliek A.M. and Spelbrink J.N. (2003) Composition and dynamics of human mitochondrial nucleoids. Mol Biol Cell 14, 1583-1596. Spelbrink J.N., Li F.Y., Tiranti V., Nikali K., Yuan Q.P., Tariq M., Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., Fabrizi G.M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., Jacobs H.T., Zeviani M., Larsson C. (2001) Human mitochondrial
Spelbrink J.N., Toivonen J.M., Hakkaart G.A.J., Kurkela, J.M., Cooper H.M., Lehtinen S.K., Lecrenier N., Back JW., Speijer D., Foury F., Jacobs H.T. (2000) In vivo functional analysis of the human mitochondrial
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