Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells.
Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells.
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DOI：
10.1038/ncb2837
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发表时间：
2013-10
影响因子：
21.3
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中科院分区：
文献类型：
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通过宏观自噬识别受损线粒体的降解对细胞健康至关重要，但其机制仍然知之甚少。心磷脂是一种线粒体内膜磷脂。我们发现在原代皮质神经元和SH-SY5Y细胞中，鱼藤酮、星形孢子素、6-羟基多巴胺和其他促有丝分裂刺激引起心磷脂外化到线粒体表面。RNAi敲除心磷脂合成酶或磷脂扰乱酶-3，将心磷脂输送到线粒体外膜，减少线粒体向自噬小体的输送。此外，我们还发现，自噬蛋白微管相关蛋白-1轻链-3(LC3)同时参与自噬小体的形成和货物识别，它含有对自噬系统吞噬线粒体至关重要的心磷脂结合位点。通过计算模型预测为心磷脂相互作用位点的LC3残基的突变抑制了它参与有丝分裂。这些数据表明，心磷脂的重新分布是消除神经细胞中受损线粒体的“吃我”信号。
Recognition of injured mitochondria for degradation by macroautophagy is essential for cellular health, but the mechanisms remain poorly understood. Cardiolipin is an inner mitochondrial membrane phospholipid. We found that rotenone, staurosporine, 6-hydroxydopamine and other pro-mitophagy stimuli caused externalization of cardiolipin to the mitochondrial surface in primary cortical neurons and SH-SY5Y cells. RNAi knockdown of cardiolipin synthase or of phospholipid scramblase-3, which transports cardiolipin to the outer mitochondrial membrane, decreased mitochondrial delivery to autophagosomes. Furthermore, we found that the autophagy protein microtubule-associated-protein-1-light chain-3 (LC3), which mediates both autophagosome formation and cargo recognition, contains cardiolipin-binding sites important for the engulfment of mitochondria by the autophagic system. Mutation of LC3 residues predicted as cardiolipin-interaction sites by computational modeling inhibited its participation in mitophagy. These data indicate that redistribution of cardiolipin serves as an “eat-me” signal for the elimination of damaged mitochondria from neuronal cells.