Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis.
Mauro CorradoFrancesca R MariottiLaura TrapaniLucia TaraborrelliFrancesca NazioValentina CianfanelliMaria Eugenia SorianoEmilie SchrepferFrancesco CecconiLuca ScorranoSilvia CampelloPublished in: The EMBO journal (2016)
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.
Keyphrases
- cell death
- cell cycle arrest
- oxidative stress
- protein kinase
- endoplasmic reticulum stress
- signaling pathway
- diabetic rats
- binding protein
- dna methylation
- gene expression
- drug induced
- cell proliferation
- gold nanoparticles
- endoplasmic reticulum
- reactive oxygen species
- stress induced
- copy number
- endothelial cells
- nlrp inflammasome
- anti inflammatory