Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders

Abstract

In addition to be the cell’s powerhouse, mitochondria also contains a cell death machinery. Indeed, after a number of new mitochondrial proteins and modulator metabolites have been discovered, this organelle has emerged as a center of attention in processes of cell signaling, cell injury and cell death. Evidence has been provided that mitochondria comprise one of the main pathways for cell death through the opening of highly regulated membrane pores, increased rates of reactive oxygen species (ROS) production, and mitochondrial DNA mutations. High levels of matrix Ca2+ stimulate ROS production and NADPH oxidation, and lead to opening of pores in the inner mitochondrial membrane (permeability transition pore, PTP). When PTP opens in a large number of mitochondria, cell death may occur due to the lack of ATP (necrosis). In addition, mitochondrial outer membrane permeabilization (MOMP) induces cell death (apoptosis) through the release of molecules that promote both caspase-dependent and caspase-independent cell death. MOMP itself can occur via processes dependent or independent of PTP opening. Mitochondrial dysfunction has been associated with several cardiac, metabolic and neurodegenerative disorders. In these states, many signal transduction molecules, toxins or experimental drugs can act either inducing opening or closing of the mitochondrial membrane pores. Taken together, it seems that mitochondrial cell death control has wide implications in cell physiology, pathology and pharmacology. We have recently demonstrated that mitochondrially-mediated redox imbalance is an important part of the pathogenesis of genetic dyslipidemias, neurodegenerative disorders, and may control the death of tumor cells. In this project we propose to carry on further investigation on the mitochondrial involvement on these conditions, expanding the elucidation of mitochondrial mechanisms that leads to cell death using in vivo and in vitro approaches. We will also investigate the mitochondrial involvement in the pathogenesis of additional neuro and cardiometabolic disorders (secondary hyperlipidemia, diabetes, hypertension, alcoholism, Alzheimer’s disease). In addition, new “omics” approaches (metabolome, lipidome and proteome) will be used to fast disclose metabolic pathways altered in the situations where mitochondrial dysfunctions were already demonstrated by us. (AU)