MITOCHONDRIAL ENERGY-PRODUCTION AND CATION CONTROL IN MYOCARDIAL-ISCHEMIA AND REPERFUSION

In the heart mitochondria exert two roles essential for cell survival: ATP synthesis and maintainance of Ca2+ homeostasis. These two process es are driven by the same energy source: the H+ electrochemical gradie nt (DELTAmuH) which is generated by electron transport along the inner mitochondrial membrane. Under aerobic physiological condition mitocho ndria do not contribute to the beat to beat regulation of cytosolic Ca 2+, although Ca2+ transient in mitochondrial matrix has been described . Increases in mitochondrial Ca2+ of mumolars concentration stimulate the Krebs cycle and NADH redox potential and, therefore, ATP synthesis . Under pathological conditions, however, mitochondrial Ca2+ transport and overload might cause a series of vicious cycles leading to irreve rsible cell damage. Mitochondrial Ca2+ accumulation causes profound al terations in permeability of the inner membrane to solutes, leading to severe mitochondrial swelling. In addition Ca2+ transport takes prece dence over ATP synthesis and inhibits utilization of DELTAmuH for ener gy production. These processes are important to understand the sequenc e of the molecular events occurring during myocardial reperfusion afte r prolonged ischaemia which lead to irreversible cell damage. During i schaemia an alteration of intracellular Ca2+ homeostasis occurs and mi tochondria are able to buffer cytosolic Ca2+, suggesting that they ret ain the Ca2+ transporting capacity. Accordingly, once isolated, even a fter prolonged ischaemia, the majority of the mitochondria is able to use oxygen for ATP phosphorylation. When isolated after reperfusion, m itochondria are structurally altered, contain large quantities of Ca2, produce excess of oxygen free radicals, their membrane pores are sti mulated and the oxidative phosphorylation capacity is irreversibly dis rupted. Most likely, reperfusion provides oxygen to reactivate mitocho ndrial respiration but also causes large influx of Ca2+ in the cytosol as result of sarcolemmal damage. Mitochondrial, Ca2+ transport is the refore stimulated at maximal rates and, as consequence, the equilibriu m between ATP synthesis and Ca2+ influx is shifted towards Ca2+ influx with loss of the ability of ATP synthesis.