ABSTRACT OF THE DISSERTATION
Mitochondrial Metabolism and Morphology
in Mitochondrial Disease States
Mariella Theresa Simon
Doctor of Philosophy in Biological Sciences
University of California, Irvine, 2016
Professor Susanne Rafelski, Chair
Mitochondria are the hub of cellular metabolism, respiration and energy production. They are sites of reactive oxidative species (ROS), heme and steroid generation. They buffer cellular calcium flux, regulate redox states, control cell cycle and death and are therefore at the nexus of human health and disease. Syndromes encountered in the mitochondrial disease clinic, associated with mutations in mitochondrial genes, are generally rare and require detailed clinical mitochondrial disease workups, including next generation sequencing technology. The discovery of new genes often presents itself with inconclusive findings, which need to be further pursued and delineated in the research setting. It is therefore of great importance to apply the “bedside to bench and back to bedside” principle in the field of mitochondrial medicine to advance diagnostic and treatment modalities. In this dissertation, I demonstrate bioenergetic findings in three novel mitochondrial disease genes, NARS2, TFAM and LonP1, in a collaborative effort. By doing so, I have helped to delineate the underlying cause of pathologies for families with mitochondrial disease. Presented are also two case studies of patients with mutations in POLG and GFM1, with unusual clinical findings, which may point to new, not yet described cellular processes associated with mitochondrial dysfunction. By correlating gene function with patient’s disease, taking into consideration clinical parameters observed, I have also shown new metabolic findings in a primary fibroblast tissue culture system from patients with mutations in the mitochondrial matrix protease LonP1. The patients have mutations in a domain of the gene, which has never been associated with disease. Findings suggest that the patient phenotype depends on the location of the mutations in LonP1 and that clinical expression is domain specific. Findings also show increased susceptibility to stress, elicited by the use of antibiotic/antimycotic in the tissue culture system. In the future, I plan to build on the results from this study, to assess the effects of potential treatment modalities on mitochondrial function in fibroblast culture.