[Programmed cell death and apoptosis. The role of mitochondria]

Physiological cell death and apoptosis are natural processes genetically programmed, subjected to control by complex molecular mechanisms which elucidation is of particular interest for biology and medicine. Mitochondria play an essential role in physiological cell death and apoptosis. Apoptogenic effects develop in three phases, namely: (a) premitochondrial; (b) mitochondrial and (c) post-mitochondrial. During the first phase, apoptogenic signals (genotoxic agents, oxygen free radicals, corticoids, antibodies, etc.) interact with cell receptors activating specific mechanisms including thiol dependent proteases (caspases). As a consequence of those signals, mitochondrial damage results (membrane permeabilization, collapse of the membrane potential, swelling, membrane disruption, inhibition of electron transfer and oxidative phosphorylation). Other consequences of the mitochondrial disruption are the enhancement of free radical production and the exit of cytochrome c, caspases and endonucleases to the cytosol. During the third phase of apoptosis, free radicals and activated enzymes attack the cell protein structure and ADN, thus causing cell death. The mitochondrial regulation of apoptosis is controlled by the mitochondrial transitory permeability pore (MTPP) which is constituted by caspases, hexokinases, cytochrome c, ATP and ADP. MTPP is subjected to control by apoptogenic or antiapoptogenic agents which open or close it, according to their structure and the cell metabolic conditions. Uncontrolled opening of MTPP determines a massive exit of mitochondrial apoptogenic factors which in the cytosol and the nucleus exert their apoptogenic effects, thus producing cell death. MTPP can be modified by drugs with potential therapeutic actions thus opening interesting therapeutic possibilities. The role of apoptosis in pathologies such as degenerative diseases of the nervous system, autoimmunity diseases, SIDA and cancer is discussed.