Induction of the mitochondrial permeability transition causes release of the apoptogenic factor cytochrome C

Joy C. Yang, Gino A Cortopassi

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

It was recently reported that the mitochondrial protein cytochrome c is required for the induction of apoptosis, and that the overexpression of Bcl- 2 caused increased retention of this apoptogenic factor by mitochondria. Several cellular toxins, including H2O2, tBOOH and Ca++, induce the Mitochondrial Permeability Transition (MPT); we tested the possibility that MPT is an intracellular sensor of toxicity that results in the release of cytochrome c. We observe that the release of eytochrome c from purified mitochondria is stimulated by the classical inducers of MPT, and is inhibited by the classical inhibitor of MPT, cyclosporin A (CsA). After induction of MPT, mitochondrial supernatants gained the activity to induce cleavage of caspase 3 (CPP32) in cytosolic extracts, and this gain of activity was inhibited by CsA pretreatment of mitochondria, and was cancelled by immunodepletion of cytochrome c from the supernatants. After induction of MPT, mitochondrial supernatants mixed with or without cytosolic extract gained the activity to ladder nuclei, and this gain of activity was inhibited by CsA pretreatment of mitochondria, and cancelled by immunodepletion of cytochrome c from the supernatants. These results demonstrate that the induction of MPT causes release of cytochrome c from mitochondria, which is required for the hallmarks of cytosolic and nuclear apoptosis, caspase 3 activation and nuclear laddering, and identify the MPT as a potential intracellular sensor of oxidants and other toxins, and as a target for the pharmacological inhibition of apoptosis.

Original languageEnglish (US)
Pages (from-to)624-631
Number of pages8
JournalFree Radical Biology and Medicine
Volume24
Issue number4
DOIs
StatePublished - Mar 1 1998

Fingerprint

Mitochondria
Cytochromes
Cytochromes c
Permeability
Cyclosporine
Apoptosis
Caspase 3
Mitochondrial Proteins
Sensors
Ladders
Oxidants
Toxicity
Chemical activation
Pharmacology

Keywords

  • Apoptosis
  • Cytochrome c
  • Free radical
  • Mitochondria
  • Permeability transition

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

Cite this

Induction of the mitochondrial permeability transition causes release of the apoptogenic factor cytochrome C. / Yang, Joy C.; Cortopassi, Gino A.

In: Free Radical Biology and Medicine, Vol. 24, No. 4, 01.03.1998, p. 624-631.

Research output: Contribution to journalArticle

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