Mammalian Mitochondrial Bioenergetics:
Energy conversion processes in mammalian cells are far from perfect. The research conducted in Dr. Harper’s laboratory focuses specifically on the metabolic pathways that affect efficiency of energy transduction processes within different cells of the body. The cellular organelle ‘charged’ with the responsibility of energy conversion is the mitochondrion. It is there that the oxidation of various energy substrates converges for the production of the universal energy currency of cells, ATP. The efficiency of mitochondrial ATP synthesis, or oxidative phosphorylation, varies between different tissues of the body; between different metabolic states; and between different disease states (e.g., thyroid disorders).
The overall aim of the research projects conducted in the Harper lab is to better understand the control of cellular energy transduction processes in health and disease.
In particular, Dr. Harper’s laboratory investigates the metabolic significance and control of uncoupling proteins (UCPs). UCPs are a subfamily of the mitochondrial carrier protein family and are located in the mitochondrial inner membrane. They have been hypothesized to cause a mitochondrial proton leak, and thereby allow protons to return to the mitochondrial matrix, bypassing ATP synthase. Thus energy substrates are oxidized, and the energy is released (or ‘wasted’) as heat, insteadof being converted to ATP. The function of such seemingly wasteful processes is a major interest of the lab. Also of interest overall are the processes in cells that ‘sense’ energy surfeit and deficit conditions – the major sensor is AMP-activated protein kinase (AMPK). The role of uncoupling proteins in the acute control of mitochondrial reactive oxygen species production is an expanding research interest of the laboratory group. The latter has great implications for cell signalling and oxidative stress. This, in turn has implications for a better understanding of such processes ranging from energy conversion efficiency in muscle, to pancreatic insulin secretion, to cellular responses to chemotherapeutic agents, to metabolic flexibility in muscle and to satiety signalling in the brain.
Dr. Harper’s research group uses integrative approaches spanning from bioenergetic studies of isolated mitochondria, to mitochondrial protein post-translational modification, to transfected cell cultures, to transgenic mice, and to clinical investigations. Clinical projects are conducted in collaboration with Dr. Robert Dent (Ottawa Hospital), and Dr. Ruth McPherson (University of Ottawa Heart Institute). Experimental techniques include: gene transfection, site-directed mutagenesis, transgenics and knockouts, fluorometric assays, oxygen and ion-selective electrodes, real-time PCR, Western blotting, and various forms of histology and microscopy.