Characterization of the Role of Mitochondrial Function During Tumor Development and Muscle Wasting

Mitochondria play important roles in multiple cellular processes including energy metabolism, cell death, and aging. Regulated energy production and utilization is critical in maintaining energy homeostasis in normal cells and functional organisms. However, mitochondria go through a series of morphological and functional alterations during carcinogenesis. The metabolic profile in transformed cells is altered to accommodate their fast proliferation, confer resistance to cell death, or facilitate metastasis. On the organism level, mitochondrial function is crucial especially in tissues that require high energy supply, such as brain and skeletal muscle. Mitochondrial dysfunction has been implied in various neurodegenerative disorders and deteriorating chronic conditions such as sepsis and cachexia. The work presented in this dissertation represents three strategies employed to study the role of mitochondrial function in tumor development, pathological and physiological muscle wasting. The peroxisome proliferator-activated receptors (PPARs) and their coactivators are major players in the regulation of mitochondrial biogenesis under diverse physiological conditions. Using in vitro and in vivo models, we have demonstrated that mitochondrial metabolism could be targeted for anti-cancer treatment, as well as that mitochondria play an important role in maintaining muscle stem cell pool and function of motor units, although simply increasing mitochondrial mass was not sufficient to protect from cancer-induced muscle wasting. In the first part of this work we showed that cancer cells treated with bezafibrate in culture had increased levels of oxidative metabolism, especially lipid metabolism. Bezafibrate is a pharmacological agent that activates PPARs and PPAR coactivator-1α (PGC-1α) pathways that have been shown to improve mitochondrial function and energy metabolism. This treatment led to decreased cancer cell growth in glycolytic medium, and impaired invasiveness due to lower levels of extracellular lactate acidification. However, a boost in mitochondrial mass with PGC-1α adenovirus infection was not able to replicate the effect we observed in bezafibrate treated cancer cells. These results indicate that a shift in the metabolic profile could be employed in combination with current anti-cancer therapies. Previous studies have implied mitochondrial dysfunction in various situations of muscle wasting. In the second part of this work we took advantage of a transgenic mouse model with increased expression of PGC-1α in skeletal muscle to test whether increasing mitochondrial content could prevent or even reverse cancer-induced cachexia. The increased mitochondrial biogenesis was maintained in tumor-bearing transgenic mice, to our surprise, this was not enough to ameliorate muscle loss phenotypes. However, a larger tumor size was associated with PGC-1α overexpression in our model and could mask the potential beneficial effects of increased mitochondrial biogenesis in skeletal muscle on preventing muscle wasting. The final part of this thesis studied the role of mitochondrial DNA (mtDNA) damage in muscle health. Using a mouse model transiently expressing a ubiquitous mitochondria-targeted restriction endonuclease we observed premature aging phenotypes in multiple organs. While the mitochondrial mass or oxidative enzyme activities were not much tampered with, we found substantial decreases in the function of neuromuscular junctions and muscle stem cell pool in mice affected by this mtDNA damage. Our results suggested mitochondrial defects, without causing massive oxidative stress, or affecting mature muscle cells, have the potential to cause age-related muscle decline, i.e. sarcopenia