The research conducted in our lab is targeted to characterize bioenergetic, respiratory and metabolic functions of mitochondria, tissues and cells and to identify the site, severity and consequences of mitochondrial dysfunction and metabolic dysregulation using polarographic, spectrophotometric, fluorescence, luminescence and biochemical techniques. Many of these are real-time analyses and include measurements of respiratory and phosphorylating activities, generation of a transmembrane potential, energized calcium uptake capabilities, swelling and induction of the membrane permeability transition, ROS generation and redox changes in cytochromes and pyridine nucleotides as well as an extensive array of conventional enzyme and metabolite assays. This lab also has a special interest in cancer cell biology, in particular the study of the metabolic reprogramming cancer cells undergo to meet bioenergetic and biosynthetic demands of increased cell proliferation.
Mitochondria play indispensable roles in cellular energy transduction, metabolism and metabolic regulation, signal transduction, growth, redox regulation and death. The integrity of mitochondrial function is fundamental to life and mitochondrial dysfunction can clearly have profound effects on cellular physiology. Understanding the consequences of mitochondrial dysfunction and metabolic dysregulation has important implications for elucidating pathogenic mechanisms, guiding diagnosis and developing therapies for a wide range of diseases including cancer, diabetes and cardiovascular and neurodegenerative diseases as well as the aging process.
This core research laboratory (1) assists with experimental design, data collection, analysis and interpretation in collaboration with other investigators doing mitochondrial research; (2) serves as a resource for theoretical and technical aspects of mitochondrial research; (3) develops new techniques and strategies to examine mitochondrial function; and (4) teaches other investigators to do mitochondrial analyses. We have collaborated/assisted with projects incorporating species ranging from humans and rodents to C. elegans, drosophila and zebra fish and tissues ranging from brain and cardiac/skeletal muscle to liver, kidney and multiple cultured cell lines. Among the projects on which we have worked include those examining mitochondrial function in a conditional pVHL knockout mouse, Pol? mutant mice, zebrafish with mutant ETFp, peripheral blood cells from Friedreich ataxia patients, AKT1 knockout mouse muscle, mouse hippocampus following traumatic brain injury and different cultured cell lines.
Alterations and consequences of mitochondrial function and cellular metabolism in normal and disease states
Mitochondria, oxidative phosphorylation, metabolism, metabolic regulation and reprogramming
Polarographic, spectrophotometric, fluorescence, luminescence and biochemical techniques
1. Simmons RA, Suponitsky-Kroyter I, Selak MA. Progressive accumulation of mtDNA mutations and decline in mitochondrial function lead to beta cell failure. J Biol Chem 280:28785-28791, 2005.
2. Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield K, Pan Y, Simon MC, Thompson CG, Gottlieb, E. Succinic acid links TCA cycle dysfunction to oncogenic events by inhibiting HIF prolyl hydroxylase. Cancer Cell 7:77-85, 2005.
3. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25:4675-4682, 2006.
4. Selak MA, Duran-Diaz R, Gottlieb E. Redox stress is not essential for the pseudo-hypoxic phenotype of succinate dehydrogenase deficient cells. Biochimica Biophysica Acta 1757:567-572, 2006.
5. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nadano K, Bartrons R, Gottlieb E, Vousden KH. TIGAR, a novel regulator of glycolysis and apoptosis, is induced by p53. Cell 126:107-120, 2006.
6. MacKenzie ED, Selak MA, Tennant D, Payne LJ, Crosby S, Frederiksen CM, Watson DG, Gottlieb E. Reactivating prolyl hydroxylase in succinate dehydrogenase-deficient cells alleviates pseudo-hypoxia. Mol Cell Biol 27:3282-3289, 2007.
7. Kundu M, LindstenT, Yang CY, Wu J, Zhao F, Zhang J, Selak MA, Ney PA, Thompson CB. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112:1493-1502, 2008.
8. Rankin EB, Rha J, Selak MA, Unger TL, Keith B, Liu Q, Haase VH. HIF-2 regulates hepatic lipid metabolism. Mol Cell Biol 29:4527-4538, 2009.
9. Tennant DA, Frezza C, MacKenzie ED, Nguyen Q-D, Zheng L, Selak MA, Roberts DL, Dive C, Watson DG, Aboagye EO, Gottlieb E. Re-activating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene 28: 4009-4021, 2009.
10. Song Y, Selak MA, Watson CT, Coutts C, Scherer PC, Panzer JA, Gibbs S, Scott MO, Willer G, Gregg RG, Ali DW, Bennett MJ, Balice-Gordon RJ. Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD). PLoS ONE 4:e8329-e8341, 2009.
- Research Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (2007 – 2010)
- PhD, Biochemistry, Hahnemann University (1980)
- BA, Biology, Adams State College (1969)