Molecular Basis of Mitochondrial Disease

ResearchCentre for Genetic Diseases > Molecular Basis of Mitochondrial Disease

genetics2Molecular Basis of Mitochondrial Disease

Research Group Head: Dr Matthew McKenzie

Mitochondria are the ‘powerhouses’ of eukaryotic cells, oxidizing sugars and fats to generate the energy molecule adenosine-5′-triphosphate (ATP). Defects in mitochondrial function can cause disease in both children and adults, and commonly affects high-energy demand tissues such as brain, heart, and liver. Unfortunately, there are no effective therapies to treat mitochondrial disorders and in many cases the disease is fatal. Dr McKenzie’s research aims to define the pathological mechanisms which underlie these diseases, in particular how disruption of mitochondrial fatty acid b-oxidation (FAO) and oxidative phosphorylation (OXPHOS) contribute to mitochondrial dysfunction.

Dr McKenzie’s group is defining the important physical interactions between FAO and OXPHOS protein complexes and determining how their disruption contributes to mitochondrial disease pathology. They are also investigating the role of various FAO proteins in the biogenesis of OXPHOS complex I (NADH:ubiquinone oxidoreductase). To do this, they use techniques such as Blue Native-PAGE and in vitro mitochondrial import assays. His group is also developing new mouse models of mitochondrial disease using ‘cybrid’ fusion technology and novel human models by reprogramming patient fibroblasts into induced pluripotent stem (iPS) cells.

Research Projects:

The assembly of mitochondrial protein complexes and defects in human disease
MicroRNA regulation of mitochondrial function

Research Group:

Dr Matthew McKenzie (Research Group Head)
Dr Chern Lim (Postdoctoral Scientist)
Ms Abena Nsiah-Sefaa (PhD Student)

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Selected publications:

Lim, S. C., Smith, K. R., Stroud, D. A., Compton, A. G., Tucker, E. J., Dasvarma, A., Gandolfo, L. C., Marum, J. E., McKenzie, M., Peters, H. L., Mowat, D., Procopis, P. G., Wilcken, B., Christodoulou, J., Brown, G. K., Ryan, M. T., Bahlo, M. & Thorburn, D. R. (2014). A Founder Mutation in PET100 Causes Isolated Complex IV Deficiency in Lebanese Individuals with Leigh Syndrome. Am. J. Hum. Genet. 94, 209-222.

Trounce, I. A., Crouch, P. J., Carey, K. T. & McKenzie, M. (2013). Modulation of ceramide-induced cell death and superoxide production by mitochondrial DNA-encoded respiratory chain defects in Rattus xenocybrid mouse cells. Biochim. Biophys. Acta 1827, 817-825.

Dickinson, A., Yeung, K. Y., Donoghue, J., Baker, M. J., Kelly, R. D., McKenzie, M., Johns, T. G. & St John, J. C. (2013). The regulation of mitochondrial DNA copy number in glioblastoma cells. Cell Death Differ. 20, 1644-53.

McKenzie, M., Tucker, E. J., Compton, A. G., Lazarou, M., George, C., Thorburn, D. R. & Ryan, M. T. (2011). Mutations in the gene encoding C8orf38 block complex I assembly by inhibiting production of the mitochondria-encoded subunit ND1. J. Mol. Biol. 414, 413-426.

#Dunning, C. J., #McKenzie, M., Sugiana, C., Lazarou, M., Silke, J., Connelly, A., Fletcher, J. M., Kirby, D. M., Thorburn, D. R., and Ryan, M. T. (2007). Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO J. 26, 3227-3237. #co-first authors