Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis
Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis
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DOI：
10.15252/embj.201593727
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发表时间：
2016-08-15
期刊：
影响因子：
11.4
通讯作者：
Campello, Silvia
中科院分区：
文献类型：
--
作者：
Corrado, Mauro;Mariotti, Francesca R.;Campello, Silvia
线粒体动力学和功能与几种应激条件下的自噬降解途径有关。然而，线粒体和自噬之间的相互作用对细胞死亡信号仍然不清楚。T细胞受体途径发出对免疫耐受调节至关重要的所谓活化诱导细胞死亡（AICD）的信号。在这里，我们表明，这种凋亡途径需要抑制大自噬。T细胞受体信号传导下游的蛋白激酶A激活抑制AICD诱导后的巨自噬。这导致受损线粒体的积累，这些线粒体被破碎，显示重塑的嵴并释放细胞色素c，从而驱动细胞凋亡。自噬强制再激活清除帕金森装饰的线粒体是有效的抑制细胞凋亡的遗传干扰嵴重塑和细胞色素c的释放。因此，在AICD诱导调节大自噬，而不是选择性线粒体自噬，确保凋亡进展。
Mitochondrial dynamics and functionality are linked to the autophagic degradative pathway under several stress conditions. However, the interplay between mitochondria and autophagy upon cell death signalling remains unclear. The T-cell receptor pathway signals the so-called activation-induced cell death (AICD) essential for immune tolerance regulation. Here, we show that this apoptotic pathway requires the inhibition of macroautophagy. Protein kinase-A activation downstream of T-cell receptor signalling inhibits macroautophagy upon AICD induction. This leads to the accumulation of damaged mitochondria, which are fragmented, display remodelled cristae and release cytochrome c, thereby driving apoptosis. Autophagy-forced reactivation that clears the Parkin-decorated mitochondria is as effective in inhibiting apoptosis as genetic interference with cristae remodelling and cytochrome c release. Thus, upon AICD induction regulation of macroautophagy, rather than selective mitophagy, ensures apoptotic progression.