Dissociation of cytochrome c from the inner mitochondrial membrane during cardiac ischemia.
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.
Czerski
Lech W
LW
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Szweda
Pamela A
PA
Szweda
Luke I
LI
D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003574:Cytochrome c Group / Q000737:chemistry* / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D007477:Ions; D007511:Ischemia; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013395:Sucrose / Q000494:pharmacology; D013997:Time Factors
D003574:Cytochrome c Group; D007477:Ions; D008353:Mannitol; D013395:Sucrose; D011189:Potassium Chloride; D010100:Oxygen