Apoptosis to necrosis switching downstream of apoptosome formation requires inhibition of both glycolysis and oxidative phosphorylation in a BCL-XL and PKB/AKT-independent fashion

D. Gramaglia, A. Gentile, M. Battaglia, L. Ranzato, V. Petronilli, M. Fassetta, P. Bernardi, Andrea Rasola

Research output: Contribution to journalArticle

Abstract

Human T-lymphoma Jurkat cells treated with several intrinsic death stimuli readily undergo a stepwise apoptotic program. Treatment with 1,9-dideoxyforskolin (ddFSK), an inactive analogue of the adenylate cyclase activator forskolin, induces necrotic cell death and switches to necrosis the response to the apoptosis inducers in Jurkat and in other cell models. Yet, in the presence of ddFSK, mitochondrial changes are enhanced and apoptosome formation takes place. We show that ddFSK does not inhibit the catabolic steps of apoptosis, but rather elicits a profound ATP depletion that in turn tunes the mode of cell demise towards necrosis. Treatment with ddFSK impairs both glycolysis and oxidative phosphorylation in a BCl-XL- and PKB/Akt-independent fashion, and inhibition of both processes is needed to affect apoptosis progression. Apoptosis is not blocked per se by ATP depletion, as engagement of the Fas receptor directly activates caspases, thus bypassing ddFSK inhibition.

Original languageEnglish
Pages (from-to)342-353
Number of pages12
JournalCell Death and Differentiation
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 2004

Keywords

  • 1,9-dideoxyforskolin
  • Apoptosis
  • Bcl-X
  • Energy metabolism
  • Necrosis
  • PKB/Akt

ASJC Scopus subject areas

  • Cell Biology

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