Dissociation of Cytochrome c from the Inner Mitochondrial Membrane during Cardiac Ischemia

Abstract

Mitochondria isolated from ischemic cardiac tissue exhibit diminished rates of respiration and ATP synthesis. The present study was undertaken to determine whether cytochrome c release was responsible for ischemia-induced loss in mitochondrial function. Rat hearts were perfused in Langendorff fashion for 60 min (control) or for 30 min followed by 30 min of no flow ischemia. Mitochondria isolated from ischemic hearts in a buffer containing KCl exhibited depressed rates of maximum respiration and a lower cytochrome c content relative to control mitochondria. The addition of cytochrome c restored maximum rates of respiration, indicating that the release of cytochrome c is responsible for observed declines in function. However, mitochondria isolated in a mannitol/sucrose buffer exhibited no ischemia-induced loss in cytochrome c content, indicating that ischemia does not on its own cause the release of cytochrome c. Nevertheless, state 3 respiratory rates remained depressed, and cytochrome c release was enhanced when mitochondria from ischemic relative to perfused tissue were subsequently placed in a high ionic strength buffer, hypotonic solution, or detergent. Thus, events that occur during ischemia favor detachment of cytochrome c from the inner membrane increasing the pool of cytochrome c available for release. These results provide insight into the sequence of events that leads to release of cytochrome c and loss of mitochondrial respiratory activity during cardiac ischemia/reperfusion.

Mitochondrial Molecular Basis of Sevoflurane and Propofol Cardioprotection in Patients Undergoing Aortic Valve Replacement with Cardiopulmonary Bypass

“…In contrast to complex IV and ATP synthase protein level, higher in sevoflurane than in propofol group, cytochrome c protein level was higher in patients receiving propofol. It has been reported that cytochrome c is detached from the inner mitochondrial membrane during cardiac ischemia/ reperfusion resulting in the loss of respiratory activity [29]. In the present study propofol receiving patients showed strong mitochondrial localization of cytochrome c, in addition to the higher protein level comparing to sevoflurane group.…”

Isoflurane preconditioning protects against ischemia-reperfusion injury partly by attenuating cytochrome c release from subsarcolemmal mitochondria in isolated rat hearts1

“…But as a small and water-soluble molecule, cytochrome c is easier to be released from mitochondria than other mitochondrial proteins. Studies have shown that the loss of cytochrome c from mitochondria could occur during ischemia and after reperfusion [9,10] . Ischemia tolerance induced by sublethal ischemia is associated with mitochondrial protection (attenuating cytochrome c release from mitochondria) in vitro and in vivo [5] .…”

Inhibition of ischemia/reperfusion-induced damage by dexamethasone in isolated working rat hearts: the role of cytochrome c release

“…Mitochondria play a central role in oxidative phosphorilation, respiratory chain, and the commitment of cells to apoptosis (Green and Kroemer, 1998;Green and Reed, 1998). Many studies show that the initial event observed following application of the apoptotic stimulus is a decrease in the inner transmembrane potential followed by an increase in the permeability of the outer mitochondrial membrane by forming the permeability transition pores and subsequent release of cytochrome c (Vanden Hoek et al, 2003;Czerski et al, 2003) from the intermembranous space into the cytosol (Goldstein et al, 2000). There may be several phases of apoptosis following reperfusion, including an initial phase following rapidly after reperfusion, an intermediate phase following neutrophil infiltration into the heart, and a delayed phase days, weeks, or months after the insult that may be involved in remodeling and cardiac failure.…”