期刊
EMBO JOURNAL
卷 35, 期 16, 页码 1793-1809出版社
WILEY
DOI: 10.15252/embj.201593727
关键词
AICD; autophagy; mitochondrial dynamics; T cells
资金
- European Commission 7th Framework Programme (FP7-PEOPLE-IEF) [235595]
- Italian Ministry of Health [GR-2011-02351643, GR 09.021]
- AIRC Program MyFAG [MFAG-12120]
- Swiss National Foundation [31-118171]
- European Research Council
- European Commission 7th Framework Programme (CRISTOPA)
- Telethon Foundation [GGP12162, GGP15198, TCR02016]
- KBVU [R72-A4408]
- Lundbeck Foundation [R167-2013-16100]
- Novo Nordisk Foundation [7559]
- AIRC
- FISM
- Fondazione Telethon [GGP14202]
- Italian Ministry of University and Research (FIRB Accordi di Programma)
- Danish National Research Foundation
- Lundbeck Foundation [R209-2015-3505, R165-2013-15982, R167-2013-16100] Funding Source: researchfish
- The Danish Cancer Society [R146-A9471] Funding Source: researchfish
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.
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