Professor Mike Ryan
Department of Biochemistry and Molecular Biology
Rm 231, 23 Innovation Walk,
Monash University, 3800
+61 3 9902 4909
Mike joined the Department of Biochemistry and Molecular Biology in 2014. Before this, he was at La Trobe University (2000-2014) including as head of the Department of Biochemistry (2010-2013). Mike has always had an interest in mitochondrial biology, starting as a PhD student with Peter Hoj and Nick Hoogenraad (La Trobe/Adelaide) and then as an Alexander von Humboldt Fellow with Klaus Pfanner (Freiburg, Germany). Mike is president of the Australian Society for Biochemistry and Molecular Biology (ASBMB) and is also a reviewing editor for the Journal of Biological Chemistry. He serves on a number of committees including as a member for the Scientific and Medical Advisory Panel for the Australian Mitochondria Disease Foundation (AMDF) and on the National Committee for Biomedical Science, AAS.
Ryan lab (2015): from left to right - Elliot Surgenor, Abeer Singh, Laura Osellame, Jo Usher, Luke Formosa, Marris Dibley, Laura Twigg, Matteo Boas, David Stroud, Mike Ryan
Mitochondria are essential organelles and are present in all of our cells. They are known as the "powerhouse" of the cell since they burn carbon to make chemical energy (ATP). They are also the "poison-cupboard" of our cells since if the mitochondrial outer membrane is opened, proteins are released that cause cell death (apoptosis). Cell death is important since as our cells divide we must kill others - otherwise cancers may arise and so this process is very well regulated.
Mitochondria are also involved in aging, reactive oxygen species production, immune responses, and defects in mitochondria are implicated in many diseases including Parkinson's disease and Alzheimer's.
Defects in the respiratory chain result in human mitochondrial disease and affect ~1/5,000 live births. Onset can be at any age, but severe childhood disease is common and symptoms regularly involve neurological and muscular disease. Defects in respiratory chain Complex I is the most common mitochondrial disease, and results in multi-system disorders. Complex I contains 44 different protein subunits, with 7 subunits encoded by mitochondrial genes and the rest by nuclear genes. Complex I failure leads to defects in aerobic respiration with elevated lactic acid and ketone bodies. Complex I is also known to generate reactive oxygen species, an important contributor to many mitochondrial pathologies. In collaboration with the Murdoch Childrens Research Institute at the Royal Children's Hospital, we analyse cells from patients for defects in assembly of the respiratory chain, in particular Complex I. Using new gene-editing techniques (TALENs and CRISPRs), we are complementing our patient studies with targeted knockouts of specific Complex I subunits and other proteins so we can understand how they help build this important molecular machine.
Mitochondria form a network that is finely tuned to the needs of the cell. Changes in mitochondrial fission and fusion are important events in cell signalling and development. However unscripted changes in the mitochondrial network can be pathological. Increased mitochondrial fission also appears to be a hallmark of disease states including Huntington's and Parkinson's and during apoptosis. We have identified two new players of mitochondrial fission, MiD49 and MiD51, involved in recruiting the master fission mediator Dynamin related protein 1 (Drp1) to mitochondria. Using imaging, cell biology and structural biology, we are working out how the MiD proteins regulate mitochondrial dynamics at the cellular and molecular level. Our findings are being used to determine how fission and fusion events may be controlled in disease states.
Functional analysis of the human mitochondrial proteome
While we understand many aspects of mitochondrial function, we still do not fully appreciate the roles played by many individual proteins present in the organelle. Of the ~1300 proteins in human mitochondria, about 30% have no known function while another 30% have been assigned functions based on sequence similarity. We are coupling gene-editing techniques (TALENs and CRISPRs) to generate gene knockouts in cultured human cells and investigating how a protein's loss impacts mitochondria and the cell. This work is being coupled with state-of-the-art proteomic and bioinformatic approaches to determine how the cell changes its protein make-up to adjust to these changes. In our approach to functionalise the human mitochondrial proteome we are making new and important discoveries into fundamental aspects related to mitochondrial protein function.
Opportunities to join the lab
Honours and PhD Projects are currently available in the laboratory. The lab uses a wide range of cell, molecular biology and protein techniques to study mitochondrial functions. Applications/enquiries can be sent by email to email@example.com.
Members of the Ryan lab
Dr David Stroud (NHMRC Doherty fellow)
Dr Laura Osellame (postdoc)
Mr Elliot Surgenor (research assistant)
Ms Laura Twigg (research assistant)
Mr Luke Formosa (PhD student)
Mr Abeer Singh (PhD student)
Mr Matteo Bonas (PhD student)
Ms Joanne Usher (honours student)
Mr Marris Dibley (honours student)
Dr Amelia Johnson (postdoc, La Trobe University)
Dr Diana Stojanovski (AvH fellow, Freiburg; now group leader, Bio21)
Dr Christopher Dunning (postdoc, Leeds)
Dr Olga Koutsopolous (postdoc, Strassbourg)
Dr Michael Baker (AvH fellow, Cologne)
Dr Laura Osellame (University College London; now Monash Uni)
Dr Michael Lazarou (postdoc, NIH Washington; now Monash Uni)
Dr Mat McKenzie (ARC Future fellow, MIMR)
Dr Ved Mooga (postdoc, USA)
Dr Kirstin Elgass (Monash Micro imaging)
Dr Xioanan Wang (La Trobe University)
Dr Catherine Palmer (Microcopy manager, Burnet Institutepostdoc)
Dr Thanh Nguyen (Lazarou lab, Monash University)
Dr Boris Reljic (postdoc, WEHI)
COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2. Stroud DA, Maher MJ, Lindau C, Vögtle FN, Frazier AE, Surgenor E, Mountford H, Singh AP, Bonas M, Oeljeklaus S, Warscheid B, Meisinger C, Thorburn DR, Ryan MT. Hum Mol Genet. 2015 Oct 1;24(19):5404-15.
Analysis of ER-mitochondria contacts using correlative fluorescence microscopy and soft X-ray tomography of mammalian cells. Elgass KD, Smith EA, LeGros MA, Larabell CA, Ryan MT. J Cell Sci. 2015 Aug 1;128(15):2795-804.
Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission.
Richter V, Singh AP, Kvansakul M, Ryan MT, Osellame LD. Cell Mol Life Sci. 2015 Oct;72(19):3695-707.
FunRich: An open access standalone functional enrichment and interaction network analysis tool. Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, Mouradov D, Sieber OM, Simpson RJ, Salim A, Bacic A, Hill AF, Stroud DA, Ryan MT, Agbinya JI, Mariadason JM, Burgess AW, Mathivanan S. Proteomics. 2015 Aug;15(15):2597-601.
Characterization of mitochondrial FOXRED1 in the assembly of respiratory chain complex I.
Formosa LE, Mimaki M, Frazier AE, McKenzie M, Stait TL, Thorburn DR, Stroud DA, Ryan MT. Hum Mol Genet. 2015 May 15;24(10):2952-65.
Mapping biological composition through quantitative phase and absorption X-ray ptychography. Jones MW, Elgass K, Junker MD, Luu MB, Ryan MT, Peele AG, van Riessen GA. Sci Rep. 2014 Oct 28;4:6796.
Neuronal and astrocyte dysfunction diverges from embryonic fibroblasts in the Ndufs4fky/fky mouse. Bird MJ, Wijeyeratne XW, Komen JC, Laskowski A, Ryan MT, Thorburn DR, Frazier AE. Biosci Rep. 2014 Nov 21;34(6):e00151.
Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: a requirement for VDAC2 or Bak for efficient Bax apoptotic function. Ma SB, Nguyen TN, Tan I, Ninnis R, Iyer S, Stroud DA, Menard M, Kluck RM, Ryan MT, Dewson G. Cell Death Differ. 2014 Dec;21(12):1925-35.
Stalking the mitochondrial ATP synthase: Ina found guilty by association. Stroud DA, Ryan MT. EMBO J. 2014 Aug 1;33(15):1617-8
Structural and functional analysis of MiD51, a dynamin receptor required for mitochondrial fission. Richter V, Palmer CS, Osellame LD, Singh AP, Elgass K, Stroud DA, Sesaki H, Kvansakul M, Ryan MT. J Cell Biol. 2014 Feb 17;204(4):477-86
A founder mutation in PET100 causes isolated complex IV deficiency in Lebanese individuals with Leigh syndrome. Lim SC, Smith KR, Stroud DA, Compton AG, Tucker EJ, Dasvarma A, Gandolfo LC, Marum JE, McKenzie M, Peters HL, Mowat D, Procopis PG, Wilcken B, Christodoulou J, Brown GK, Ryan MT, Bahlo M, Thorburn DR. Am J Hum Genet. 2014 Feb 6;94(2):209-22.
Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression. Tucker EJ, Wanschers BF, Szklarczyk R, Mountford HS, Wijeyeratne XW, van den Brand MA, Leenders AM, Rodenburg RJ, Reljić B, Compton AG, Frazier AE, Bruno DL, Christodoulou J, Endo H, Ryan MT, Nijtmans LG, Huynen MA, Thorburn DR. PLoS Genet. 2013 Dec;9(12):e1004034.
Mitochondria: organization of respiratory chain complexes becomes cristae-lized. Stroud DA, Ryan MT. Curr Biol. 2013 Nov 4;23(21):R969-71.
Adaptor proteins MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and are specific for mitochondrial fission. Palmer CS, Elgass KD, Parton RG, Osellame LD, Stojanovski D, Ryan MT. J Biol Chem. 2013 Sep 20;288(38):27584-93.
Assembly of the Bak apoptotic pore: a critical role for the Bak protein α6 helix in the multimerization of homodimers during apoptosis. Ma S, Hockings C, Anwari K, Kratina T, Fennell S, Lazarou M, Ryan MT, Kluck RM, Dewson G. J Biol Chem. 2013 Sep 6;288(36):26027-38.
Gene Knockout Using Transcription Activator-like Effector Nucleases (TALENs) Reveals That Human NDUFA9 Protein Is Essential for Stabilizing the Junction between Membrane and Matrix Arms of Complex I. Stroud DA, Formosa LE, Wijeyeratne XW, Nguyen TN, Ryan MT. J Biol Chem. 2013 18;288(3):1685-90. Rated Best of JBC 2013
Mitochondrial dysfunction in a novel form of autosomal recessive ataxia. Murad NA, Cullen JK, McKenzie M, Ryan MT, Thorburn D, Gueven N, Kobayashi J, Birrell G, Yang J, Dörk T, Becherel O, Grattan-Smith P, Lavin MF. Mitochondrion. 2012 Nov 22. doi:pii:S1567-7249(12)00254-1.
Impaired folding of the mitochondrial small TIM chaperones induces clearance by the i-AAA protease. Baker MJ, Mooga VP, Guiard B, Langer T, Ryan MT, Stojanovski D. J Mol Biol. 2012 Dec 14;424(5):227-39.
Mitofusins 'bridge' the gap between oxidative stress and mitochondrial hyperfusion. Ryan MT, Stojanovski D. EMBO Rep. 2012 Oct;13(10):870-1.
Recent advances into the understanding of mitochondrial fission. Elgass K, Pakay J, Ryan MT, Palmer CS. Biochim Biophys Acta. 2013 Jan;1833(1):150-61.
Proteomic and Metabolomic Analyses of Mitochondrial Complex I-deficient Mouse Model Generated by Spontaneous B2 Short Interspersed Nuclear Element (SINE) Insertion into NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (Ndufs4) Gene. Leong DW, Komen JC, Hewitt CA, Arnaud E, McKenzie M, Phipson B, Bahlo M, Laskowski A, Kinkel SA, Davey GM, Heath WR, Voss AK, Zahedi RP, Pitt JJ, Chrast R, Sickmann A, Ryan MT, Smyth GK, Thorburn DR, Scott HS. (2012) J Biol Chem. 287, 20652-63.
Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy. Ke BX, Pepe S, Grubb DR, Komen JC, Laskowski A, Rodda FA, Hardman BM, Pitt JJ, Ryan MT, Lazarou M, Koleff J, Cheung MM, Smolich JJ, Thorburn DR. (2012) Proc Natl Acad Sci U S A. 109, 6165-70.
Next Generation Sequencing in molecular diagnosis: NUBPL mutations highlight the challenges of variant detection and interpretation. Tucker EJ, Mimaki M, Compton AG, McKenzie M, Ryan MT, Thorburn DR. 2012 Human Mutat. Feb;33(2):411-8.
Understanding mitochondrial complex I assembly in health and disease. Mimaki M, Wang X, McKenzie M, Thorburn DR, Ryan MT. Biochim Biophys Acta. 2011 Mar;1808(3):1002-11.
Mutations in the Gene Encoding C8orf38 Block Complex I Assembly by Inhibiting Production of the Mitochondria-Encoded Subunit ND1. McKenzie M, Tucker EJ, Compton AG, Lazarou M, George C, Thorburn DR, Ryan MT. 2011 J Mol Biol. 2;414(3):413-26.
Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Tucker EJ, Hershman SG, Köhrer C, Belcher-Timme CA, Patel J, Goldberger OA, Christodoulou J, Silberstein JM, McKenzie M, Ryan MT, Compton AG, Jaffe JD, Carr SA, Calvo SE, RajBhandary UL, Thorburn DR, Mootha VK. Cell Metab. 2011 Sep 7;14(3):428-34.
The regulation of mitochondrial morphology: intricate mechanisms and dynamic machinery. Palmer CS, Osellame LD, Stojanovski D, Ryan MT. Cell Signal. 2011 Oct;23(10):1534-45. Review.
MiD49 and MiD51, new components of the mitochondrial fission machinery. Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT. EMBO Rep. 2011 Jun;12(6):565-73.
Inhibition of Bak activation by VDAC2 is dependent on the Bak transmembrane anchor. Lazarou M, Stojanovski D, Frazier AE, Kotevski A, Dewson G, Craigen WJ, Kluck RM, Vaux DL, Ryan MT. J Biol Chem. 2010 Nov 19;285(47):36876-83.
Mitochondrial protein import machineries and lipids: A functional connection. Gebert N, Ryan MT, Pfanner N, Wiedemann N, Stojanovski D. Biochim Biophys Acta. 2010 Aug 7.
Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M, Compton A, Lim SC, Thorburn D, Ryan MT, Giegé R, Bahlo M, Christodoulou J. Am J Hum Genet. 2010 Jul 9;87(1):52-9.
Assembly factors of human mitochondrial complex I and their defects in disease. Mckenzie M, Ryan MT. IUBMB Life. 2010 Jul;62(7):497-502.
Human Miltons associate with mitochondria and induce microtubule-dependent remodeling of mitochondrial networks. Koutsopoulos OS, Laine D, Osellame L, Chudakov DM, Parton RG, Frazier AE, Ryan MT. Biochim Biophys Acta. 2010 May;1803(5):564-74.
Mitochondrial cardiolipin involved in outer-membrane protein biogenesis: implications for Barth syndrome. Gebert N, Joshi AS, Kutik S, Becker T, McKenzie M, Guan XL, Mooga VP, Stroud DA, Kulkarni G, Wenk MR, Rehling P, Meisinger C, Ryan MT, Wiedemann N, Greenberg ML, Pfanner N. Curr Biol. 2009 Dec 29;19(24):2133-9
Assembly of nuclear DNA-encoded subunits into mitochondrial complex IV, and their preferential integration into supercomplex forms in patient mitochondria. Lazarou M, Smith SM, Thorburn DR, Ryan MT, McKenzie M. FEBS J. 2009 276(22): 6427 - 6824
Chapter 18 Analysis of respiratory chain complex assembly with radiolabeled nuclear and mitochondrial encoded subunits. McKenzie M, Lazarou M, Ryan MT. Methods Enzymol. 2009. 456:321-39.
Assembly of mitochondrial complex I and defects in disease. Lazarou M, Thorburn DR, Ryan MT, McKenzie M. Biochim Biophys Acta. 2009 1793(1):78-88.
Structural and functional requirements for activity of the Tim9-Tim10 complex in mitochondrial protein import. Baker MJ, Webb CT, Stroud DA, Palmer CS, Frazier AE, Guiard B, Chacinska A, Gulbis JM, Ryan MT. Mol. Biol. Cell. 2009 20(3):769-79.
National Health and Medical Research Council of Australia
Australian Mitochondrial Disease Foundation