A Systems-Level Investigation of the Genetic and Phenotypic Heterogeneity of Mitochondrial Disorders

Abstract

Mitochondrial diseases are a diverse set of phenotypically and genetically heterogeneous disorders. This thesis explores these two themes using a systems approach. One chapter focuses on phenotypic heterogeneity and tissue-specificity by combining existing cancer cell line sequencing and expression data with a pharmacologic screen. Through this approach, we prioritized genes involved in mitochondrial biogenesis and the AKT signaling pathway with sensitivity or resistance to mitochondrial dysfunction. Another chapter investigates a potential complex genetic basis for disease in patients with mitochondrial disorders lacking a molecular diagnosis. We applied existing biological knowledge about protein complexes and metabolic pathways to identify sets of variants in multiple genes that could combine to cause disease, spotlighting Complex I of the respiratory chain and enzymes involved in fatty acid beta-oxidation. Understanding the phenotypic and genetic heterogeneity of diseases is a question that extends beyond the mitochondrial disorders; we hope that these approaches can also be applied to other conditions to characterize the complex interactions underlying human pathophysiology.