Science, Technology and Engineering

Hoogenraad Laboratory

Department of Biochemistry

Research – Mitochondrial-Nuclear Communications and Biomarker Discovery and Translation into Diagnostic and Therapeutic Products

Hoogenraad lab 2011

The research interests of the laboratory fall into two categories:

(1) Mitochondrial-Nuclear Communications

• the role of molecular chaperones in protein targeting to mitochondria
• characterization of a mitochondrial unfolded protein response

(2) Biomarker Discovery and Translation into Diagnostic and Therapeutic Products

Mitochondrial-Nuclear Communications

The role of molecular chaperones in protein targeting to mitochondria

Mitochondria are organelles which are essential for the viability of cells. These contain the machinery for the generation of most of the cells energy, but also play essential roles in the synthesis of compounds needed by the cell and contain critical regulators of apoptosis.

Our interests have centred on the mechanism of import of proteins into mitochondria of mammalian cells, particularly the role of molecular chaperones in this process and the broader function of mitochondria. We have isolated many of the chaperones of the mitochondrial matrix of mammalian cells and the components of the translocation complex through which proteins are imported. We have isolated cDNA and genes encoding these and have carried out extensive functional studies on these components.
We have also recently discovered a mechanism for targeting of pre-proteins to mitochondria. In this process, two cytosolic chaperones Hsp70 and Hsp90 co-operate to deliver pre-proteins to mitochondria via a docking mechanism with one of the import receptors of the translocation complex (Young, Hoogenraad and Hartl (2003) Cell 112, 41-50). The involvement of Hsp90 in this process is a new, surprising finding, which has major implications in understanding the way in which pre-protein import is regulated in mammalian cells (Fig).

Characterization of a mitochondrial unfolded protein response

Our work on mitochondrial chaperones led us to discover a Mitochondrial Unfolded Protein Response (also called a Mitochondrial Stress response; Zhao et al  2002, EMBO J.) where the accumulation of unfolded proteins within mitochondria results in the up-regulation of genes encoding mitochondrial chaperones and proteases which combine to return the mitochondria to a normal functional state. We have found that in mitochondria from mammalian cells the accumulation of unfolded proteins leads initially to the signalling between mitochondria and the nucleus, leading to the activation of a large number of genes encoding quality control proteins (chaperones and proteases) through an extended promoter element which incorporates a CHOP element (figure).

Biomarker Discovery and Translation into Diagnostic and Therapeutic Products.

The lab is involved in a program of research to identify changes in protein profiles of immune   and cancer cells in response to disease. This work is a proteomics project supported by the Co-operative Research Centre (CRC) for Diagnostics (until June 31, 2007) and from July 1, the CRC for Biomarker Translation. This research is a partnership between major Australian laboratories and international partners, Becton Dickinson and Amgen.

Research  in the laboratory is broadly based on cell biology, recombinant DNA technology and protein chemistry. Students or postdoctoral fellows wishing to work in the lab can choose from projects that have a major emphasis in molecular biology to projects which are mainly in the protein chemistry area. However, essentially all projects involve the full range of techniques encompassed by these disciplines.