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.

Corrado, M., Mariotti, F.r., Trapani, L., Taraborrelli, L., Nazio, F., Cianfanelli, V., et al. (2016). Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis. EMBO JOURNAL, 35(16), 1793-1809 [10.15252/embj.201593727].

Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis

Nazio F.;Cianfanelli V.;Cecconi F.;Campello S.
2016

Abstract

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/13
English
Con Impact Factor ISI
AICD; T cells; autophagy; mitochondrial dynamics; Animals; Cells, Cultured; Cytochromes c; Humans; Mice, Inbred C57BL; Mitochondria; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes; Apoptosis; Autophagy
Corrado, M., Mariotti, F.r., Trapani, L., Taraborrelli, L., Nazio, F., Cianfanelli, V., et al. (2016). Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis. EMBO JOURNAL, 35(16), 1793-1809 [10.15252/embj.201593727].
Corrado, M; Mariotti, Fr; Trapani, L; Taraborrelli, L; Nazio, F; Cianfanelli, V; Soriano, Me; Schrepfer, E; Cecconi, F; Scorrano, L; Campello, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/191219
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