Mitochondrial dysfunction in metabolic diseases
Mitochondria are unique and complex organelles that carry out critical metabolic functions within the cells. Once considered to be mere sites of ATP generation, it is now evident that these organelles participate in a wide range of cellular processes including calcium homeostasis, apoptosis, redox balance or cell fate. Because of this multifaceted contribution of mitochondria to key biologic and metabolic pathways it is not surprising that mitochondrial dysfunction has been linked to many human disorders including neurodegeneration, diabetes, cancer or aging.
Specifically, our lab focuses on defects in the oxidative phosphorylation system (OXPHOS) occurring from mitochondrial disease mutations that compromise cellular fitness and survival. This biochemical failure is
thought to underlie pathologies associated with mitochondrial dysfunction. However, the precise metabolic processes, signaling pathways and compensatory responses resulting from a defective mitochondrial Electron Transport Chain (ETC) that drive these fatal disorders are not entirely understood. Although diminished ATP production has been considered a hallmark of mitochondrial dysfunction, our recent discoveries highlighted that other metabolic failures such as disturbed redox hemostasis due to accumulated levels of NADH can be equally detrimental. Moreover, which cell types contribute the most to the disease and whether disease-carrying cells negatively impact the function of its surrounding wild-type neighbors or distant organs remain poorly characterized.
The long-tern goal of our lab is to understand the molecular components that regulate mitochondrial metabolism, in the context of physiology and diseases, and use this knowledge to develop successful therapies.
We are currently exploring two central areas. First, we aim to elucidate the molecular mechanisms whereby mitochondrial dysfunction compromise cellular fitness and leads to organ failure in the context of human diseases. Second, we focus on understanding the metabolic vulnerabilities of metastasizing cancer cells and to define novel therapeutic approaches to prevent cancer progression.
To accomplish these goals, we are employing cutting-edge technologies such CRISPR/Cas9-based genetic screenings, multi-omics platform, single cell clonal tracking and preclinical mouse models