Reactive γ-ketoaldehydes formed via the isoprostane pathway disrupt mitochondrial respiration and calcium homeostasis
Reactive γ-ketoaldehydes formed via the isoprostane pathway disrupt mitochondrial respiration and calcium homeostasis
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DOI：
10.1016/j.freeradbiomed.2010.04.037
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发表时间：
2010-08-15
影响因子：
7.4
通讯作者：
Kristal, Bruce S.
中科院分区：
文献类型：
--
作者：
Stavrovskaya, Irina G.;Baranov, Sergei V.;Kristal, Bruce S.
异酮醛(IsoKs)是通过花生四烯酸过氧化的异前列腺素途径形成的伽马酮醛，是脂质过氧化反应最活跃的副产物之一。IsoK选择性地与蛋白质赖氨酸残基加成，具有高度的细胞毒性，但IsoK诱导细胞死亡的靶点和分子事件尚不明确。我们之前的工作证实，生理上相关的醛导致线粒体功能障碍(Kristal等人，J.Biol。化学。271：6033-6038；1996)。因此，我们研究了IsoKs是否导致线粒体功能障碍。在Ca(2+)存在或不存在的情况下，线粒体与合成的IsoKs孵育与线粒体呼吸、膜电位(Delta Psi)和吡啶核苷酸氧化还原状态的变化有关。IsoKs剂量依赖性地(0.5-4mU M)促进低浓度Ca(2+)、Zn(2+)或氧化剂叔丁基氢过氧化氢诱导的肝线粒体肿胀和细胞色素c的释放，心脏/脑线粒体也有类似的观察结果。线粒体通透性转换(MPT)抑制剂环孢素A延缓了IsoK诱导的线粒体功能障碍。IsoKs的作用与细胞色素c的相互作用是一致的，细胞色素c是一种富含赖氨酸残基的蛋白质。用高分辨质谱仪证实了IsoKs与细胞色素c中部分赖氨酸的直接反应。总体而言，这些结果表明，IsoKs可能部分地通过诱导MPT和随后激活下游细胞死亡级联来调节其细胞毒效应。(C)2010 Elsevier Inc.保留所有权利。
Isoketals (IsoKs) are gamma-ketoaldehydes formed via the isoprostane pathway of arachidonic acid peroxidation and are among the most reactive by-products of lipid peroxidation. IsoKs selectively adduct to protein lysine residues and are highly cytotoxic, but the targets and molecular events involved in IsoK-induced cell death are poorly defined. Our previous work established that physiologically relevant aldehydes induce mitochondrial dysfunction (Kristal et al., J. Biol. Chem. 271:6033-6038; 1996). We therefore examined whether IsoKs induced mitochondrial dysfunction. Incubation of mitochondria with synthetic IsoKs in the presence or absence of Ca(2+) was associated with alterations in mitochondrial respiration, membrane potential (Delta Psi), and pyridine nucleotide redox state. IsoKs dose dependently (0.5-4 mu M) accelerated liver mitochondria swelling induced by low concentrations of Ca(2+) and Zn(2+) or by the prooxidant tert-butylhydroperoxide, and release of cytochrome c, with similar observations in heart/brain mitochondria. The mitochondrial permeability transition (mPT) inhibitor cyclosporine A delayed IsoK-induced mitochondria dysfunction. The actions of IsoKs are consistent with interactions with cytochrome c, a protein rich in lysine residues. Direct reaction of IsoKs with select lysines in cytochrome c was demonstrated using high-resolution mass spectrometry. Overall, these results suggest that IsoKs may, in part, mediate their cytotoxic effects through induction of the mPT and subsequent activation of downstream cell death cascades. (C) 2010 Elsevier Inc. All rights reserved.