Regulation of the cardiac mitochondrial membrane potential by retinoids.
Cardiomyocytes suffering irreversible damage under oxidative stress during ischemia activate their suicide program. Mitochondria play a key role in this process, while they themselves are subject to regulation by a number of signaling pathways. We demonstrate here that retinoids influence mitochondrial function in cardiomyocytes. Depending on their chemical nature, retinoids can either ameliorate or exacerbate stress-related damage. Thus, vitamin A, retinol, was protective because retinol deprivation enhanced oxidative damage, as indicated by rapid loss of mitochondrial membrane potential. Supplementation with a physiological concentration of retinol reversed this effect. Anhydroretinol (AR), a known antagonist, which works by displacing retinol from the common binding sites on serine/threonine kinases, also caused mitochondrial membrane depolarization. The AR effect was both Ca(2+)-dependent and cyclosporin-sensitive, suggesting an upstream signaling mechanism rather than direct membrane effect. Our results agree with a model where retinol supports mitochondrial integrity by enabling upstream signaling processes. The consequences of disrupting these processes by AR are opening of the permeability transition pore, release of cytochrome c, and activation of the suicide program.
Korichneva
Irina
I
Program in Immunology, Sloan-Kettering Institute for Cancer Research, 1275 York Ave., New York, NY 10021, USA. korichni@mskcc.org
Waka
John
J
Hammerling
Ulrich
U
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D006861:Hydrogen Peroxide / Q000633:toxicity; D007476:Ionophores; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D012176:Retinoids / Q000494:pharmacology*
D000199:Actins; D007476:Ionophores; D017382:Reactive Oxygen Species; D012176:Retinoids; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D006861:Hydrogen Peroxide