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.
Highlights
We have previously reported that, in an isolated rat heart model, ischemia results in inhibition of complex I with no alterations in other respiratory chain complex activities [11]
The decline in state 3 respiratory rates in mitochondria isolated in either KCl or mannitol/sucrose-based buffers indicates ischemia results in mitochondrial alterations that prevent cytochrome c from carrying out efficient electron transport and promote cytochrome c release in KCl buffers
We provide evidence that ischemia-induced declines in the rate of mitochondrial respiration and ATP synthesis are due, at least in part, to decreased association of cytochrome c with the inner mitochondrial membrane
Summary
We have previously reported that, in an isolated rat heart model, ischemia results in inhibition of complex I with no alterations in other respiratory chain complex activities [11]. Release of respiratory chain components during ischemia may be overlooked as contributing factors in the loss of mitochondrial respiration when standard assays for complex activities are utilized One such electron transport chain component is was enhanced when mitochondria from ischemic rela- cytochrome c, a protein required for the transfer of electrons tive to perfused tissue were subsequently placed in a from complexes III to IV. Events that occur during ischemia favor de- rat heart model to investigate mechanism(s) by which mitotachment 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.
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