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Dr Mike Ryan (La Trobe University) |
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Dr Mike Ryan
B.Sc. (La Trobe), PhD (La Trobe)
Senior Lecturer in Biochemistry
Phone: +61 3 9479 2156/1175 (Lab)
Fax: +613 9479 2467
Email: [email protected]
Homepage: www.latrobe.edu.au/biochemistry/labs/ryan/research.html
Room 369 (Office), 365 (Lab),
Physical Sciences 4 |
Research in our laboratory focuses on mitochondrial biogenesis. Mitochondria are the primary site of cellular ATP synthesis, and as such are essential for cell viability. They are also important in Ca2+ homeostasis and apoptosis, making them a key target for pharmacological intervention in a range of pathologies. Mitochondria are not created de novo, but require the constant synthesis of mitochondrial and nuclear-encoded proteins for their biogenesis.
Mitochondrial morphology and distribution
In mammalian cells mitochondria are generally found as a reticulated network radiating from the nucleus with individual mitochondria displaying morphological and functional heterogeneity (see picture). Their diversity in form reflects a multiplicity of roles in cell development and differentiation. Sperm cells, for example, contain elongate mitochondria wrapped in a helical sheath around the axoneme complex to provide ATP for flagellum movement, whilst pancreatic acinar cells exist in three functionally unconnected mitochondrial populations that sense and discriminate between Ca2+ signals in the immediate environment.
Although the mechanisms by which mitochondria undergo structural changes within a cell are not known, they are primarily affected by (i) fusion and fission events, and (ii) interaction with cytoskeletal elements, kinesin and attachment proteins. We are characterising a number of molecules involved in mitochondrial morphology and distribution.
We have recently identified a mitochondrial outer membrane protein, called Fis1, that regulates mitochondrial morphology (Stojanovski et al., 2004). Fis1 is involved in mitochondrial fission - its overexpression causes mitochondrial fragmentation while knockdown blocks fission and causes mitochondrial fusion to continue unopposed. This leads to the formation of abnormally long mitochondrial tubules. Fis1 works with other proteins in this process, including the dynamin-related protein, Drp1, which seemingly polymerises around mitochondrial tubules and facilitates fission.
Respiratory chain Complex I and mitochondrial disease.
Complex I (NADH-Ubiquinone oxidoreductase) of the mitochondrial respiratory chain is a ~900 kDa complex containing 45 different subunits in humans, 7 of which are encoded by mtDNA. The remaining 38 nuclear encoded proteins are translated in the cytosol and must be imported into the organelle. Thus, mechanisms must be in place that co-ordinate and regulate the assembly of nuclear and mtDNA encoded Complex I subunits into the functional complex. Little information is so far known about the assembly and turnover of human Complex I.
Mitochondria diseases occur ~1/5,000 live births with defects in Complex I being the most prevalent. Complex I deficiency often results in multi-system disorders with a fatal outcome. We believe that in some cases, Complex I deficiency can be attributed to defects in the cellular machinery involved in the assembly of Complex I. We are investigating the biogenesis of Complex I and identifying the machinery involved in its assembly. Through a collaboration with Dr David Thorburn from the Murdoch Children's Research Institute (Royal Children’s Hospital), we are examining skin cells from patients with mitochondrial disease to determine whether Complex I assembly defects are present.
Protein import into mitochondria
While the mitochondrion contains its own DNA and protein synthesis machinery, it produces only few polypeptides itself. Most proteins are actually synthesised in the cytosol and are subsequently imported into this organelle. The first step of preprotein recognition at the mitochondrial surface is performed through the interaction with members of the translocase of the outer membrane (TOM). Preproteins are first bound to TOM receptor subunits such as Tom20 and Tom70 and are then transferred to TOM components that make up the General Import Pore. Preproteins are subsequently translocated across the outer membrane through the pore protein Tom40 before engaging with the translocase components of the inner membrane (TIM).
We are interested in understanding the process of mitochondrial protein import in mammals and how the different translocase machineries operate. This work will not only contribute to our understanding of this essential process, but will provide a means for future research into targeting of apoptotic factors to the mitochondria and the analysis of diseases that arise from defects in protein import into mitochondria.
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