Gogvadze V, Klein S D, Shigenaga M, Ames B N, Richter C
Department of Molecular and Cell Biology, University of California, Berkeley, USA.
Redox Rep. 2000;5(6):359-63. doi: 10.1179/135100000101535924.
The seleno-organic compound ebselen mimics the glutathione-dependent, hydroperoxide reducing activity of glutathione peroxidase. The activity of glutathione peroxidase determines the rate of hydroperoxide-induced Ca2+ release from mitochondria. Ebselen stimulates Ca2+ release from mitochondria, accelerates mitochondrial respiration and uncoupling, and induces mitochondrial swelling, indicating a deterioration of mitochondrial function. These manifestations are abolished by cyclosporine A, a potent inhibitor of the mitochondrial permeability transition. However, when ebselen-induced Ca2+ cycling is prevented with ruthenium red, an inhibitor of the Ca2+ uniporter, or by chelation of extramitochondrial Ca2+ by EGTA, no detectable elevation of swelling or uncoupling is observed. The release of Ca2+ from mitochondria is delayed in the absence of rotenone, i.e. when pyridine nucleotides are maintained in the reduced state due to succinate-driven reversed electron flow. We suggest that ebselen induces Ca2+ release from intact mitochondria via an NAD+ hydrolysis-dependent mechanism.
有机硒化合物依布硒啉可模拟谷胱甘肽过氧化物酶依赖谷胱甘肽的过氧化氢还原活性。谷胱甘肽过氧化物酶的活性决定了过氧化氢诱导的线粒体Ca2+释放速率。依布硒啉刺激线粒体释放Ca2+，加速线粒体呼吸和解偶联，并诱导线粒体肿胀，表明线粒体功能恶化。这些表现可被环孢素A消除，环孢素A是线粒体通透性转换的有效抑制剂。然而，当用钌红（一种Ca2+单向转运体抑制剂）或通过EGTA螯合线粒体外Ca2+来阻止依布硒啉诱导的Ca2+循环时，未观察到肿胀或解偶联的可检测升高。在没有鱼藤酮的情况下，即当由于琥珀酸驱动的逆向电子流使吡啶核苷酸保持还原状态时，线粒体Ca2+的释放会延迟。我们认为依布硒啉通过依赖NAD+水解的机制诱导完整线粒体释放Ca2+。
