title: Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis.
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.
authors.affiliation: Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Corrado
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Mariotti
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Trapani
authors.affiliation: Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: Lucia
authors.initials: L
authors.lastname: Taraborrelli
authors.affiliation: Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Nazio
authors.affiliation: Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cianfanelli
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Soriano
authors.affiliation: Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy Department of Biology, University of Padova, Padova, Italy.
authors.forename: Emilie
authors.initials: E
authors.lastname: Schrepfer
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy Department of Biology, University of Rome Tor Vergata, Rome, Italy Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy Department of Biology, University of Padova, Padova, Italy.
authors.forename: Luca
authors.identifier: 0000-0002-8515-8928
authors.initials: L
authors.lastname: Scorrano
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy Department of Biology, University of Rome Tor Vergata, Rome, Italy silvia.campello@uniroma2.it.
authors.forename: Silvia
authors.identifier: 0000-0003-0536-2484
authors.initials: S
authors.lastname: Campello
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D045304:Cytochromes c
keywords: AICD; T cells; autophagy; mitochondrial dynamics