Early mitochondrial alterations in ATRA-induced cell death.
All-trans retinoic acid (ATRA) induces differentiation and subsequent apoptosis in a variety of cell lines. Using the myeloid cell line P39, we show that ATRA disturbs mitochondrial functional activity long before any detectable signs of apoptosis occur. These early changes include diminished mitochondrial oxygen consumption, decreased calcium uptake by mitochondria and as a result, a lower mitochondrial matrix calcium concentration. Granulocyte colony-stimulating factor (G-CSF) increases mitochondrial respiration and calcium accumulation capacity and subsequently blocks ATRA-induced apoptosis. Nifedipine, a plasma membrane calcium channel blocker, inhibits apoptosis-related changes, such as the loss of the mitochondrial membrane potential and activation of caspases. Thus, the properties of ATRA and G-CSF to modulate mitochondrial respiration and intracellular calcium control are novel findings, which give insight into their precise molecular mode of action.
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden. Jan.Schmidt-Mende@medhs.ki.se
J
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Schmidt-Mende
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Gogvadze
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Hellström-Lindberg
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Zhivotovsky
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009543:Nifedipine / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D014212:Tretinoin / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin; D020169:Caspases; D009543:Nifedipine; D002118:Calcium