Mitochondria and Neurodegeneration Group

• 
  
  Associate Professor Ian A Trounce

  i.trounce@unimelb.edu.au

  View researcher's webpage

  +61 3 8532-1964

Project Details

Defective mitochondrial function is increasingly recognized as a primary pathogenic driver in a diverse range of neurodegenerative diseases. Primary mitochondrial optic neuropathies are a central focus of the group's work, where retinal ganglion cells and their axons (which form the optic nerve) are the main affected cell type. These include Leber Hereditary Optic Neuropathy (LHON) and Autosomal Dominant Optic Atrophy (ADOA). We are also pursuing the hypothesis that a sub-group of the most common age-related optic neuropathy, glaucoma, may have a mitochondrial etiology. Our group also collaborates with other neuroscientists studying  Parkinson's and Alzheimer disease.

Our research tools and models are centred on mitochondrial genetics, biochemistry and cell biology. Mitochondrial DNA (mtDNA) replication and transcription leads to the production of key protein subunits of the energy generating pathway of oxidative phosphorylation (OXPHOS). Unique in the eukaryotic cell, OXPHOS complexes are assembled from both the mtDNA-encoded and many nuclear encoded protein subunits. We use high resolution respirometry, to measure maximal OXPHOS function. We can then trace defects in OXPHOS to nuclear or mtDNA-encoded candidates using cybrid technology, where mtDNAs are transferred between cells. Transfer of defects into cybrids can demonstrate mtDNA linkage of such defects. Both mtDNA and nuclear gene defects are well established in mitochondrial diseases. Unique to our laboratory is the use of transmitochondrial mice, taking the cybrid approach to in vivo studies of mtDNA-linked disease. A full range of cell biology techniques is also employed in our lab, to investigate the mechanisms of mitochondrial disease in  patient-derived samples.

Current and ongoing research projects include identification of genetic modifiers of LHON penetrance using patient-derived cells; exploration of mtDNA variation in glaucoma; nuclear epigenetic responses to OXPHOS dysfunction using cybrids; and Parkinson's disease modeling in a xenomitochondrial mouse unique to our lab. We also study how underlying genetically-linked mitochondrial dysfunction may worsen common diseases including diabetic complications.

Researchers

Dr Isabel Lopez Sanchez, PhD, Postdoctoral Fellow

Ms Sheridan Keene, Laboratory Manager

Collaborators

Professor Jonathan Crowston, Head of Glaucoma Research, CERA.
A/Professor Alice Pebay and Dr Raymond Wong, CERA.
Professor Justin St John, Dr Mat McKenzie, Hudson Institute.
Dr Peter Crouch, University of Melbourne (Pathology)
Dr James Duce, University of Melbourne (Florey)
Professor Mark Cooper, Baker-IDI
Professor Assim El-Ostra, Baker-IDI
Professor Doug Wallace, University of Pennsylvania
Professor Nicholas Marsh-Armstrong, University of California Davis

Funding

NHMRC;
Ophthalmic Research Institute of Australia (ORIA);
Juvenile Diabetes Research Foundation (USA);
Michael J. Fox Foundation for Parkinson's Disease/Shake It Up! Australia;
DHB Foundation (Perpetual Trustees)
Mason Foundation (ANZ Trustees)

Research Publications

Lopez Sanchez MIG, Crowston JG, Mackey DA, Trounce IA. Emerging therapeutic targets in mitochondrial optic neuropathies. Pharmacology and Therapeutics 2016; (epub Jun 21)
Lim SC, Hroudová J, Van Bergen NJ, Lopez Sanchez MIG, Trounce IA, McKenzie M. Loss of the Mitochondrial DNA-encoded protein ND1 results in the disruption of Complex I biogenesis during the early stages of its assembly. FASEB J 2016; 30(6):2236-48.  
Coughlan MT, Nguyen TV, Penfold SA, Higgins GC, Thallas-Bonke V, Tan SM, Van Bergen NJ, Sourris KC, Harcourt BE, Thorburn DR, Trounce IA, Cooper ME, Forbes JM. Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. Clinical Sci. 2016; 130(9):711-20.
Picard M, Zhang J, Hancock S, Derbeneva O, Golhar R, Golik P, O'Hearn S, Levy S, Potluri P, Lvova M, Davila A, Lin CS, Perin JC, Rappaport EF, Hakonarson H, Trounce IA, Procaccio V, Wallace DC. Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. Proc Natl Acad Sci (USA) 2014; 111(38):E4033-42.
Kelly RD, Rodda AE, Dickinson A, Mahmud A, Nefzger CM, Lee W, Forsythe J, Polo JM, Trounce IA, McKenzie M, Nisbet DR, St John JC. Mitochondrial DNA haplotypes define gene expression patterns in pluripotent and differentiating embryonic stem cells. Stem Cells. 2013; 31:703-716.
Lee S, Sheck L, Crowston JG, Van Bergen N, O’Neill EC, O’Hare F, Kong Y-XG, Chrysostomou V, Vincent AL, Trounce IA.  Impaired Complex-I-Linked respiration and ATP Synthesis in Primary Open-Angle Glaucoma Patient Lymphoblasts. Invest Ophthalmol Vis Sci 2012; 53:2431–2437.
Liddell JR, Donnelly PS, Lim S-C, Paterson BM, Cater MA, Savva MS, Mot AI, James JL, Trounce IA, White AR, Crouch PJ. An impaired mitochondrial electron transport chain increases cellular retention of the hypoxia imaging agent CuII(atsm). Proc Natl Acad Sci (USA) 2012; 109:47-52.
Van Bergen N, Crowston JG, Kearns L, Staffieri S, Cohn A, Hewitt A, Mackey DA, Trounce IA.
Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked Autosomal Dominant Optic Atrophy. PLoS One 2011; 6(6)e21347.
Mackey D, Trounce I. Optic nerve genetics – more than meets the eye. Nat Rev Neurol  2010; 6:357-8.  
Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li Q-X, Barnham KJ, Curtain CC, Cherny RA, Cappai R, Dyrks T, Masters CL & Trounce IA.  Copper-dependant inhibition of human cytochrome c oxidase by a dimeric conformer of A1-42. J Neurosci 2005; 25:672-679
McKenzie M, Trounce IA, Cassar C and Pinkert CA.  Production of homoplasmic xenomitochondrial mice.  Proc Natl Acad Sci (USA) 2004; 101:1685-1690.

Full publication listing:
http://www.ncbi.nlm.nih.gov/sites/myncbi/1nE0co3oAukQL/bibliograpahy/50296768/public/?sort=date&direction=descending