Identification of genetic determinants and pharmacological modulators of mitochondrial function

Increased life expectancy goes hand in hand with a higher incidence of age-related diseases that affect the nervous and metabolic systems, such as type 2 diabetes, cancer, Parkinson’s and Alzheimer’s disease. These complex diseases are a product of the combined actions of large networks of genes, and environmental factors, such as diet, exercise, drug use, and levels of acute and chronic stress. One of the main challenges in biomedical research is determining how these factors interact to influence human healthspan, in order to develop effective strategies for the diagnosis, prevention, and treatment of these chronic multifactorial diseases. A strategy that has emerged in the last decade is the modulation of mitochondrial function. Accumulating evidence support the involvement of mitochondrial dysfunction in the pathogenesis of type 2 diabetes, Parkinson’s disease, cancer, and to a lesser extent, Alzheimer’s disease. Mitochondrial processes are regulated by a highly dynamic and complex network of enzymes and transcription factors. One of the best characterized branches of this network is the AMPK/SIRT1 pathway and its downstream effectors. Recently, additional pathways important for the regulation of mitochondrial function have been described such as mitochondrial fusion and fission, specific autophagy of mitochondria, termed mitophagy, and mitochondrial unfolded protein response (UPRmt). These recent discoveries have extended the scope of potential therapeutic targets. This thesis describes the development of two complementary approaches to identify novel genetic and pharmacological determinants of mitochondrial function. 1. The first approach aims to identify novel genetic determinants of the regulatory networks that control metabolism in general, and mitochondrial function in particular, by using the mouse BXD genetic reference population (GRP). Chapter II summarizes the analysis of 140 metabolic traits in 42 BXD strains, and demonstrates the suitability and usefulness of the BXD GRP for the identification of genetic regulators of metabolism. 2. The second approach is focused on the development of pharmacological tests for the identification and characterization of novel drugs that modulate mitochondrial phenotypes. Chapter III presents the establishment and validation of a platform of mitochondrial assays in two species, i.e. mammalian cells and the worm C.elegans. A successful example of its use is shown in chapter IV, where the role of copper in tumorigenesis is elucidated by applying these mitochondrial assays Altogether, these two synergistic approaches pave the way that will lead to the identification of novel key factors and treatments for mitochondrial diseases and pathologies associated with mitochondrial dysfunction.