Contact Details:

Robert W Taylor PhD, FRCPath
Mitochondrial Research Group
The Medical School
Newcastle University
Framlington Place
Newcastle upon Tyne
NE2 4HH
UK

Telephone: +44-191-2824375
Fax: +44191-2824373
r.w.taylor@ncl.ac.uk or
Robert.Taylor5@ nuth.nhs.uk

Links:
http://www.ncl.ac.uk/iah/staff/profile/r.w.taylor
http://www.ncl.ac.uk/ihg/services/mds/
http://cmgsweb.shared.hosting.zen.co.uk/BPGs/
Best_Practice_Guidelines.htm

Key Publications:

1. Whittaker, R.G., Blackwood, J.K., Alston, C., Blakely, E.L., Elson, J.L., McFarland, R., Chinnery, P.F., Turnbull, D.M. and Taylor, R.W. Urine heteroplasmy level is the best predictor of clinical outcome in patients with the m.3243A>G mtDNA mutation. Neurology 2008, in press.

2. Blakely, E.L.., Trip, S.A., Swalwell, H., He, L., Wren, D.R., Rich, P., Turnbull, D.M., Omer, S.E. and Taylor, R.W. A new mitochondrial tRNAPro gene mutation associated with MERRF and other neurological features. Arch. Neurol. 2008, in press.

3. Stewart, J.D., Tennant, S., Powell, H., Pyle, A.., Blakeley, E.L., He, L., Hudson, G., Roberts, M., du Plessis, D., Gow, D., Mewasingh, L.D., Hanna, M.G., Omer, S., Morris, A.A., Roxburgh, R., Livingston, J., McFarland, R., Turnbull. D.M., Chinnery, P.F. and Taylor, R.W. Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. J. Med. Genet. 2008, in press.

4. Blakely, E.L., He, L., Gardner, J.L., Hudson, G., Walter, J., Hughes, I., Turnbull, D.M. and Taylor, R.W. Novel mutations in the TK2 gene associated with fatal mitochondrial DNA depletion myopathy. Neuromusc. Disord. 2008;18:557-560.

5. Hudson, G., Amati-Bonneau, P., Blakely, E.L., Stewart, J.D., He, L., Schaefer, A.M., Griffiths, P.G., Ahlqvist, K., Suomalainen, A., Reynier, P., McFarland, R., Turnbull, D.M., Chinnery, P.F. and Taylor, R.W. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain 2008;131:329-337

6. Sebastiani, M., Giordano, C., Nediani, C., Travaglini, C., Borchi, C., Zani, M., Feccia, M., Mancini, M., Petrozza, V., Cossarizza, A., Gallo, P., Taylor, R.W. and d’Amati, G. Induction of mitochondrial biogenesis is a maladaptive mechanism in cardiac remodeling. J. Am. Coll. Card. 2007;50:1362-1369.

7. Bender, A., Krishnan, K.J., Morris, C.M., Taylor, G.A., Reeve, A.K., Perry, R.H., Jaros, E., Hersheson, J., Betts, J., Klopstock, T., Taylor, R.W., Turnbull, D.M. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genet. 2006;38:515-517.

8. Taylor, R.W., Turnbull, D.M. Mitochondrial DNA mutations in human disease. Nature Rev. Genet. 2005;6:389-402.

Professor Robert Taylor

Professor of Mitochondrial Pathology and Consultant Clinical Scientist, Newcastle University

Robert Taylor

Mitochondrial DNA mutations in human disease

Mitochondria are ubiquitous organelles, present in all nucleated cells and are the major generators of cellular ATP by the process of oxidative phosphorylation (OXPHOS). Key components of the OXPHOS complexes are encoded by the mitochondrial genome (mtDNA), the only extrachromosomal DNA molecule in mammalian cells. Human mtDNA is a maternally-inherited, circular double-stranded DNA molecule of 16.6kb which is present in cells in multiple copies. It encodes 37 contiguous genes –13 key OXPHOS polypeptides together with the necessary RNA machinery (2 rRNAs and 22 tRNAs) for their translation within mitochondria. Mutations within the mitochondrial genome or in nuclear genes encoding structural proteins, assembly factors or enzymes which maintain and replicate mtDNA are increasingly recognised as important causes of human genetic disease, and are associated with an impressive spectrum of clinical presentations in which muscle and CNS involvement are prominent. Research activities in my laboratory are divided into 3 main areas.

NCG-funded Clinical and Diagnostic Service for Rare Mitochondrial Disorders of Adults and Children

We recently led a successful application to the NHS National Commissioning Group (NCG) to provide a national, clinical and diagnostic service for patients with mitochondrial disease. This multi-disciplinary service was designated in April 2007 and encompasses all aspects of diagnosis (muscle biopsy, histochemistry, biochemistry and molecular genetics), utilising specialist clinical and laboratory skills available at the three component centres – the Newcastle upon Tyne Hospitals NHS Foundation Trust together with UCLH NHS Foundation Trust and Oxford Radcliffe Hospitals NHS Trust. Each centre has an international reputation for clinical research in the field of mitochondrial disease, and NCG funding will ensure that this research is translated into improved care for patients with mitochondrial disease. The laboratories maintain a close interaction to ensure a full-range of both mtDNA and nuclear-mitochondrial genetic tests are offered, and have recently updated the Best Practice Guidelines for the investigation of mitochondrial genetic disease in the UK. Further information on any of the laboratory services available through the three NCG centres is available from Professor Taylor, who is Head of the Newcastle diagnostic laboratory.

Molecular mechanisms underlying mitochondrial DNA and nuclear-mitochondrial genetic disease

The identification and characterisation of novel mtDNA mutations allows us to explore the underlying molecular mechanisms by which these mutations cause respiratory chain deficiency using a variety of molecular and cell biology (transferring mtDNA mutations into cybrid cells with control nuclear background) techniques, with the aim of understanding the processes involved in disease pathogenesis and the correlations between mitochondrial genotype and clinical phenotype. These investigations are performed in collaboration with a number of international groups in the United States, Italy and Australia.

Due to mtDNA heteroplasmy – the presence of both mutated and wild-type mtDNA within the same cell – the diagnosis of patients relies on the study of affected tissues such as skeletal muscle, which can exhibit characteristic pathological changes as a consequence of mtDNA abnormalities. We are also exploring non-invasive, alternatives to muscle biopsy (e.g. urinary epithelial cells) to understand the tissue-specific expression and segregation of mtDNA mutations as well as improving the molecular genetic diagnosis of patients.

Role of mtDNA mutations in ageing and other pathologies

We have a long-standing interest in the understanding the role and accumulation of somatic mtDNA mutations in ageing tissues, in both rapidly dividing cells such as human colonic crypt stem cells and also post-mitotic tissues such as brain and muscle. Ongoing studies in this area are exploring the potential of using mtDNA mutations as biomarkers of DNA damage and colorectal cancer risk, as well as determining the extent and spectrum of mtDNA mutation accumulation in other human tissues. We are also interested in the role of secondary mtDNA mutation in other muscle pathologies including inflammatory muscle disease, and have recently reported mitochondrial histochemical and genetic abnormalities associated with mutation of the OPA1 gene. With Professor Turnbull, we are also exploring exercise-based strategies for treating patients with heteroplasmic mtDNA disorders, assessing the molecular changes at the single cell level in patient muscles following endurance and resistance based training regimes.