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

Mauro Corrado, Francesca R. Mariotti, Laura Trapani, Lucia Taraborrelli, Francesca Nazio, Valentina Cianfanelli, Maria Eugenia Soriano, Emilie Schrepfer, Francesco Cecconi, Luca Scorrano, Silvia Campello

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1793-1809
Number of pages17
JournalEMBO Journal
Volume35
Issue number16
DOIs
Publication statusPublished - Aug 15 2016

Keywords

  • AICD
  • autophagy
  • mitochondrial dynamics
  • T cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Corrado, M., Mariotti, F. R., Trapani, L., Taraborrelli, L., Nazio, F., Cianfanelli, V., Soriano, M. E., Schrepfer, E., Cecconi, F., Scorrano, L., & Campello, S. (2016). Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis. EMBO Journal, 35(16), 1793-1809. https://doi.org/10.15252/embj.201593727