Ph.D, University of Alberta
Energy generation is a vital process for cellular health. Most aerobic organisms use oxidative phosphorylation in mitochondria to meet the majority of their energy needs. Oxidative phosphorylation is performed by the 4 electron transporting proteins of the mitochondrial respiratory chain (MRC) and the ATP synthase. The MRC is the major cellular source of ATP and impaired energy production leads to a bewildering variety of disease conditions, such as myopathies and encephalomyopathies, heart disease, diabetes, and degenerative syndromes such as Parkinson's disease. MRC function is also intimately linked to aging; the MRC is the major site of reactive oxygen species (ROS) production. ROS can damage proteins, DNA, and other macromolecules and it is the accumulation of damage that is associated with the age-related decline in function.
The nematode Caenorhabditis elegans is an excellent model system for investigating the molecular mechanisms of mitochondrial disease and of aging. It is an anatomically simple animal for which a wealth of genetic and developmental information is available. MRC formation requires the expression of 2 genomes, the nuclear and the mitochondrial DNAs (mtDNA). The structure and bioenergetics of the nematode MRC are very similar to the mammalian MRC and the nematode mtDNA is similar in size and gene content to the human mtDNA.
Our goal is to understand the central role of the MRC in cellular health, disease and longevity. We selective isolated and characterize both nDNA and mtDNA mutations. We model human MRC mutations in C. elegans and investigate their mechanisms of pathogenesis. MRC dysfunction results in the impairment of ATP production, the impairment of metabolism and metabolic pathways that control the redox state of the cell, in the production of excess ROS, in the aberrant control of programmed cell death (apoptosis), in premature aging and in aberrant gene expression. Each of these processes contributes to the overall disease pathology and progression. We have employed pharmacological agents and gene therapy to mitigate or correct the effects of MRC dysfunction. Mitochondrial activity is intimately linked to lifespan determination. Signaling along several pathways can extend nematode lifespan and we have shown that these pathways converge on mitochondrial function. We are actively pursuing how the regulation of mitochondrial energy generation is associated with extended lifespan.
Expression of Saccharomyces cerevisiae Sdh3p and Sdh4p paralogs results in catalytically active succinate dehydrogenase isoenzymes.
Szeto SS, Reinke SN, Oyedotun KS, Sykes BD, Lemire BD.
J Biol Chem. (2012) Jun 29;287(27):22509-20.
1H NMR-based metabolic profiling reveals inherent biological variation in yeast and nematode model systems.
Szeto SS, Reinke SN, Lemire BD.
J Biomol NMR (2011) 49:245-254.
Caenorhabditis elegans diet significantly affects metabolic profile, mitochondrial DNA levels, lifespan and brood size.
Reinke SN, Hu X, Sykes BD, Lemire BD.
Mol Genet Metab (2010) 100:274-282.
C. elegans longevity pathways converge to decrease mitochondrial membrane potential.
Lemire BD, Behrendt M, DeCorby A, Gášková D.
Mech Ageing Dev. (2009) 130:461-465.
Mutations in the C. elegans succinate dehydrogenase iron-sulfur subunit promote superoxide generation and premature aging.
Huang J, Lemire BD.
J Mol Biol. (2009) 387:559-569.
The role of mitochondria in the life of the nematode, Caenorhabditis elegans.
Tsang WY, Lemire, BD.
Biochim. Biophys. Acta (2003) 1638:91– 105.