Åsa B. Gustafsson
Associate Professor, Pharmaceutical Sciences
Ph.D., University of California, San Diego
Cardiac myocytes are highly active cells that require large amounts of energy supplied by mitochondrial oxidative phosphorylation. Since mitochondria are critical to myocyte function, it is not surprising that there is a strong link between mitochondrial dysfunction and cardiovascular disease. Defective mitochondria can also activate of cell death pathways which can lead to loss of cardiac myocytes and reduced ability to sustain contractile function. This ultimately contributes to the development of heart failure. Therefore, the ability of the cell to overcome mitochondrial damage requires removal of the impaired mitochondria via autophagy. Autophagy is an evolutionarily conserved process involved in the degradation of long-lived proteins and organelles. My lab is interested in understanding the signaling pathways pathways that regulate mitochondrial function and turnover in cardiac myocytes.
In addition, anthracyclines are among the most effective chemotherapeutic agents, but they are problematic because they are associated with cardiotoxicity. Cardiac stem cells provide a mechanism for minor repair and ongoing cell turnover in the heart. Our data suggest that anthracyclines impair stem cell function, resulting in a heart that is more susceptible to stress. We are currently investigating exactly how anthracylines interfere with stem cell function.
Huang, C., Zhang, X., Kim, L., Rikka, S., Gude, N.A., Ramil, J., Thistlethwaite, P.A., Sussman, M.A., Gottlieb, R.A., and Gustafsson, Å.B. Juvenile Anthracycline Treatment Contributes to Heart Failure in Adulthood by Impairing Vascularization and Cardiac Stem Cell Function. Circulation 121(5): 675-83, 2010.
Borillo G.A., Mason M, Quijada P, Völkers M, Cottage C, McGregor M, Din S, Fischer K, Gude N, Avitabile D, Barlow S, Alvarez R, Truffa S, Whittaker R, Glassy M.S., Gustafsson, Å.B., Miyamoto S, Glembotski C.C., Gottlieb R.A., Brown J.H., Sussman M.A., Pim-1 Kinase Protects Mitochondrial Integrity in Cardiomyocytes. Circ Res. 106(7):1265-74, 2010.
Quinsay, M.N., Thomas, R.L., Lee Y., and Gustafsson, Å.B. Bnip3-Mediated Mitochondrial Autophagy is Independent of the Mitochondrial Permeability Transition Pore. Autophagy 6(7), 2010.
Rikka, S., Quinsay, M.N., Thomas, R.L., Kubli, D.A., Zhang, X., Murphy, A.N., and Gustafsson, Å.B., Bnip3 Impairs Mitochondrial Bioenergetics and Stimulates Mitochondrial Turnover. Cell Death Diff. 18(4): 721-31, 2011.
Lee, Y., Lee, H.Y., Hanna, R.A. and Gustafsson, Å.B. Mitochondrial Autophagy by Bnip3 Involves Drp1-Mediated Mitochondrial Fission and Recruitment of Parkin in Cardiac Myocytes. Am J Physiol Heart Circ Physiol. 301(5): H1924-31, 2011.
Hanna, R.A., Quinsay, M.N., Orogo, A.M., Giang, K., Rikka, S., and Gustafsson, Å.B. Microtubule-associated Protein 1 Light Chain 3 (LC3) Interacts with Bnip3 Protein to Selectively Remove Endoplasmic Reticulum and Mitochondria via Autophagy. J Biol Chem. 287(23): 19094-19104, 2012.
Kubli, D.A., Zhang X, Lee Y, Hanna R.A., Quinsay M.N., Nguyen C.K., Jimenez R, Petrosyan S, Murphy A.N., Gustafsson, Å.B. Parkin Deficiency Exacerbates Cardiac Injury and Reduces Survival Following Myocardial Infarction. J Biol Chem. 288(2): 915-26, 2013.
Thomas, R.L., Roberts, D.J., Kubli, D.A., Lee, Y., Quinsay, M.N., Owens, J.B., Fischer, K.M., Sussman, M.A., Miyamoto, S., Gustafsson, Å.B., Loss of MCL-1 Leads to Impaired Autophagy and Rapid Development of Heart Failure. Genes & Dev. 27(12):1365-77, 2013.