Mitochondrial function and dysfunction: implications for aging and associated diseases

Abstract

In the last 40 years, it has become evident that mitochondria are involved in many cell functions besides energy conversion, such as the control of cell death via calcium and oxygen and nitrogen reactive species signaling. Elevated levels of calcium in the mitochondrial matrix stimulate the generation of reactive oxygen which promote the opening of an unspecific pore in the inner mitochondrial membrane, the Permeability Transition Pore (PTP). Opening of PTP and mitochondrial redox state alterations are associated with cell senescence and death, as well as with the progression of degenerative diseases and with aging. In addition, there is compelling evidence that further studies on the control of PTP opening in aging may open avenues to a better understanding of factors determining longevity. Therefore, the major goal of this project is to advance the knowledge about the mechanisms by which mitochondria exert their regulatory roles in cell life and death and in aging. For this purpose, we plan to use several models (mice, rats, Caenorhabditis elegans, turtles and trypanosomes) to study mitochondrial functions involved in calcium homeostasis, redox (um)balance, longevity, aging and aging-related diseases. The specific objectives are grouped in four research lines: I) nicotinamide nucleotides transhydrogenase, energy metabolism and cell viability; II) mitochondria, dyslipidemias, Atherosclerosis and Obesity; III) mitochondria and aging; and IV) mitochondria and calcium homeostasis in trypanosomatides. Each model will be used to answer specific hypotheses in an integrated and multidisciplinary way with the participation of all principal investigators and collaborators. (AU)