Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c

T. Kuwana, J. J. Smith, M. Muzio, V. Dixit, D. D. Newmeyer, S. Kornbluth

Research output: Contribution to journalArticlepeer-review

Abstract

Apoptosis often involves the release of cytochrome c from mitochondria, leading to caspase activation. However, in apoptosis mediated by CD95 (Fas/APO-1), caspase-8 (FLICE/MACH/Mch5) is immediately activated and, in principle, could process other caspases directly. To investigate whether caspase-8 could also act through mitochondria, we added active caspase-8 to a Xenopus cell-free system requiring these organelles. Caspase-8 rapidly promoted the apoptotic program, culminating in fragmentation of chromatin and the nuclear membrane. In extracts devoid of mitochondria, caspase-8 produced DNA degradation, but left nuclear membranes intact. Thus, mitochondria were required for complete engagement of the apoptotic machinery. In the absence of mitochondria, high concentrations of caspase-8 were required to activate downstream caspases. However, when mitochondria were present, the effects of low concentrations of caspase-8 were vastly amplified through cytochrome c- dependent caspase activation. Caspase-8 promoted cytochrome c release indirectly, by cleaving at least one cytosolic substrate. Bcl-2 blocked apoptosis only at the lowest caspase-8 concentrations, potentially explaining why CD95-induced apoptosis can often evade inhibition by Bcl-2.

Original languageEnglish
Pages (from-to)16589-16594
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number26
DOIs
Publication statusPublished - Jun 26 1998

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Apoptosis induction by caspase-8 is amplified through the mitochondrial release of cytochrome c'. Together they form a unique fingerprint.

Cite this