Our research program is devoted to the study of "Mitochondrial Biogenesis and Turnover in Health and Disease". We are particularly focused on studying mitochondria in mammalian skeletal muscle.
Memme, Jonathan M., Avigail T. Erlich, Geetika Phukan and David A. Hood. Exercise and mitochondrial health. J. Physiology 00.0 p. 1-15, 2019.
Mitochondrial health with age and exercise.
Mitochondrial health is an important mediator of muscle function across the lifespan, and it contributes to whole-body vitality in health and disease. Our understanding of the regulation and function of these organelles is of great interest to scientists and clinicians across many disciplines within our healthcare system. Skeletal muscle is a useful model tissue for the study of mitochondrial adaptations because of its mass and contribution to whole body metabolism. The remarkable plasticity of mitochondria allows them to adjust their volume, structure, and capacity under conditions such as exercise, aging or muscle disuse. Mitochondria exist within muscle as a functional reticulum composed of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial fractions which are maintained by dynamic processes of biogenesis and fusion, and balanced by opposing processes of fission and mitophagy (the life cycle). The coordination of these events is incompletely understood, but is imperative for organelle function and essential for the maintenance of an interconnected organelle network that is finely tuned to the metabolic needs of the cell.
Elucidation of the mechanisms of mitochondrial turnover in muscle could offer potential therapeutic targets for the advancement of health and longevity among our aging populations. As well, investigating exercise modalities that are both convenient and capable of inducing robust mitochondrial adaptations are useful in fostering more widespread global adherence. Exercise remains the most potent behavioural therapeutic approach for the improvement of mitochondrial health, not only in muscle, but potentially also in other tissues, as we age.
More specifically, a major focus of our work continues to be on studying the individual pathways within the mitochondrial life cycle, and how they are regulated with exercise, disuse and aging. These include 1) signaling events, 2) the transcriptional and post-transcriptional regulation of nuclear-encoded genes that regulate mitochondrial turnover, 3) import of proteins into the organelles, 4) mitochondrially-mediated apoptosis, 5) the regulation of mitochondrial morphology via fission and fusion, and 6) mitophagy, as mediated by lysosomal activity.
Physiological, biochemical, microscopy and molecular biology techniques are employed to study mitochondrial turnover. Most of our research makes use of animal models or cell culture techniques. However, we have active collaborations with scientists at other universities and this helps us to obtain human muscle samples from healthy or diseased patients for the investigation of mitochondria. In addition, in collaboration with other members of the Muscle Health Research Centre (MHRC), we can acquire human muscle samples using the muscle biopsy technique.
Memme, Jonathan M., Avigail T. Erlich, Geetika Phukan and David A. Hood. Exercise and mitochondrial health. J. Physiology 00.0 p. 1-15, 2019.
Regulation of mitochondrial life cycle with exercise and age.
Exercise induces changes in mitochondrial content and quality that are beneficial for metabolic health. (A) During exercise, increased cytosolic Ca2+ prompts crossbridge cycling, and the hydrolysis of ATP, as well as the generation ROS from respiring mitochondria. These events activate the signaling kinases that converge on transcriptional regulators such as PGC-1a (B) allowing translocation to the nucleus to increase the expression of NuGEMPS, such as the mtDNA transcription factor, Tfam. (C) Newly expressed nuclear-derived proteins are then imported into mitochondria through translocases of the outer, and then inner membranes (TOM and TIM, respectively). (D) The exercise stimulus increases protein synthesis within mitochondria, which promotes the activation of the UPRmt. The cleavage of terminally misfolded protein aggregates in the matrix and the release of their peptide fragments, block ATF5 mitochondrial entry, thus redirecting it to the nucleus to upregulate transcription of mitochondrial chaperones and proteases and equip the organelle with an augmented capacity for protein folding. (E) Mitochondrial fusion proteins Mfn1/2 along with Opa1 facilitate the fusion of the outer and inner membranes, respectively, allowing for improved sharing of metabolites amongst neighbouring organelles. (F) Regions of the mitochondrial network may become dysfunctional and require segregation from the reticulum. These damaged organelles undergo fission, allowing for their clearance via mitophagy. (G) Once separated, dysfunctional mitochondria with a low DY accumulate PINK1 on their outer membrane. PINK1 recruits Parkin, which subsequently ubiquitinates outer membrane proteins to flag the organelle for removal via mitophagy. The adapter protein p62 binds to the ubiquitin on the tagged cargo as well as LC3-II, embedded in the phagophore membrane, and promotes the formation of the autophagosome, which fuses with the lysosome to degrade the mitochondria and release the constituent amino acids for cellular recycling. (H) Aged muscle displays attenuated PGC-1a signalling for mitochondrial biogenesis (red line), as well as increased fission: fusion protein ratio (green line), thus promoting a fragmented network of organelles, as well as suppressed mitophagy flux during exercise.
In addition to the description provided above, each of my students has briefly described their individual projects in the "Lab Members" section of this website.
Research Impact
The information that emerges from our research will help us to understand the regulation of mitochondrial turnover in muscle subject to physiological conditions (e.g. exercise, disuse, aging). From a practical standpoint, this work informs us about how exercise can improve muscle performance, prevent disease and improve our quality of life. From a clinical perspective, our research provides us with a better understanding of the molecular basis of skeletal muscle mitochondrial myopathies, and the aging process.
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Research funding and infrastructure
Our research is funded by NSERC (Mitochondrial Biogenesis is Skeletal Muscle), CIHR (Mitochondria and lysosomal biogenesis in Aging Muscle) and the Canada Research Chairs Program.
We have >2000 square feet of space that includes major sections devoted to cell culture, animal surgery, confocal microscopy, radioactive experiments, muscle fiber sectioning, electrophoresis and immunoblotting, muscle function analyses, flow cytometry and molecular biology, as well as computer stations for data analyses.
Professional Affiliations
We are members of both the Canadian Society for Exercise Physiology (CSEP), the American Physiological Society (APS) and the American College of Sports Medicine (ACSM). We regularly attend and present papers at the annual meetings of these societies.
