Mitochondrial energy production and cation control in myocardial ischaemia and reperfusion

Abstract

In the heart mitochondria exert two roles essential for cell survival: ATP synthesis and maintainance of Ca2+ homeostasis. These two processes are driven by the same energy source: the H+ electrochemical gradient (delta microH) which is generated by electron transport along the inner mitochondrial membrane. Under aerobic physiological condition mitochondria do not contribute to the beat to beat regulation of cytosolic Ca2+, 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 irreversible cell damage. Mitochondrial Ca2+ accumulation causes profound alterations in permeability of the inner membrane to solutes, leading to severe mitochondrial swelling. In addition Ca2+ transport takes precedence over ATP synthesis and inhibits utilization of delta microH for energy production. These processes are important to understand the sequence of the molecular events occurring during myocardial reperfusion after prolonged ischaemia which lead to irreversible cell damage. During ischaemia an alteration of intracellular Ca2+ homeostasis occurs and mitochondria are able to buffer cytosolic Ca2+, suggesting that they retain the Ca2+ transporting capacity. Accordingly, once isolated, even after prolonged ischaemia, the majority of the mitochondria is able to use oxygen for ATP phosphorylation. When isolated after reperfusion, mitochondria are structurally altered, contain large quantities of Ca2+, produce excess of oxygen free radicals, their membrane pores are stimulated and the oxidative phosphorylation capacity is irreversibly disrupted. Most likely, reperfusion provides oxygen to reactivate mitochondrial respiration but also causes large influx of Ca2+ in the cytosol as result of sarcolemmal damage. Mitochondrial Ca2+ transport is therefore stimulated at maximal rates and, as consequence, the equilibrium between ATP synthesis and Ca2+ influx is shifted towards Ca2+ influx with loss of the ability of ATP synthesis.

Relation of myocardial oxygen consumption and function to high energy phosphate utilization during graded hypoxia and reoxygenation in sheep in vivo.

“…The diminished measured rephosphorylation rate represents an average throughout the myocardial area under study, and could reflect either partial decoupling in all cells or total irreversible decoupling in some cells with others unaffected. Furthermore, the transient nature of this abnormality cannot be verified, although excess Ca2+ is eventually cleared from isolated mitochondria (38) and myocytes (45) and P:02 is not diminished in glycolytically inhibited perfused hearts after ischemia (46). This study demonstrates that myocardial high energy phosphate depletion can occur during hypoxia without associated decreases in cardiac function or oxygen consumption.…”

“…Respiratory uncoupling does occur consistently in isolated mitochondria and cell preparations, which have been exposed to anoxia or hypoxia and are reoxygenated or reperfused (38). Such mitochondrial dysfunction is closely linked to increased membrane permeability (39), which results in transient accumulations of mitochondrial Ca2' during the immediate reoxygenation period (38,40,41). Oxidation is then preferentially coupled to Ca2+ transport over ATP synthesis, thus diminishing the P:02 value.…”

“…Oxidation is then preferentially coupled to Ca2+ transport over ATP synthesis, thus diminishing the P:02 value. Permeabilization of the mitochondrial membrane may be mediated through processes activated by inorganic phosphate, decreasing pH, and oxidative stress (38,39,42). Mitochondrial Ca2' accumulation also leads to loss of respiratory chain complexes (43) and enzymes (44), and partial depolarization of the mitochondrial membrane (40) with a reduction in membrane proton electrochemical potential (39).…”

Role of oxidative stress in alterations of mitochondrial function in ischemic-reperfused hearts

“…cardiac performance; oxidative phosphorylation; mitochondrial respiration; oxyradicals; antioxidants BY VIRTUE OF THEIR ABILITY to carry on the processes of oxidative phosphorylation and electron transport, mitochondria are the major source of energy production in the form of ATP, which is required for cardiac contraction and relaxation (19,26,46). Mitochondria are also known to accumulate a substantial amount of Ca 2ϩ and are considered to serve as a sink to maintain the intracellular concentration of free Ca 2ϩ within certain limits (18,19,26). However, an excessive amount of intracellular Ca 2ϩ results in the overloading of mitochondria with Ca 2ϩ…”

“…Mitochondria are also known to accumulate a substantial amount of Ca 2ϩ and are considered to serve as a sink to maintain the intracellular concentration of free Ca 2ϩ within certain limits (18,19,26). However, an excessive amount of intracellular Ca 2ϩ results in the overloading of mitochondria with Ca 2ϩ , which impairs mitochondrial energy production under different pathophysiological conditions (18,19,28).…”