Institute of Molecular Biology
My research interests have and continue to focus on the structure and function of mitochondria in health and disease. Briefly, mitochondria function broadly in cell metabolism, including in glucose metabolism (Krebs cycle and oxidative phosphorylation), in fatty acid oxidation, and in nitrogen metabolism (via the urea cycle). They are also involved in cell signaling, and are key to initiation of autophagy and apoptosis. Further, mitochondrial dysfunction is now known to be central to Alzheimers, Parkinsons, diabetes and cancer, and there are also several genetic diseases of mtDNA.
Our ongoing work is focused mainly on the ATP Synthase. This enzyme is now known to be present on the plasma membrane in many cells as well as in mitochondria.
The levels of the ectopic ATP synthase are highest in cancer cells where the enzyme acts to modulate cytosolic pH in the acid environment of the tumor. It is present in high levels on liver cells and acts as an HDL receptor. Levels are also high in endothelial cells of blood vessels. Here the ectopic ATP synthase is sensitive to shear force, which releases a subunit of the enzyme to modulate blood pressure. Further, in neuronal cells the ectopic ATP synthase has been identified as a receptor for beta amyloid (in Alzheimers disease) and for viruses such as HIV/AIDS.
We want to know more about how a large enzyme complex, in which some of the subunits are encoded on mtDNA and made on ribosomes inside mitochondria, gets to the plasma membrane. Also, we are screening for compounds that can selectively modulate the various properties of the ectopic ATP synthase with the aim of treating the several human conditions in which the enzyme plays an important role.
ATP synthase molecules (red) on the surface of an osteosarcoma cell. Mitochondria are labeled by incorporation of GFP. (From Yonelly S and Capaldi RA. (2006)).
(pulled from pubmed)