Release of cytochrome c and activation of pro-caspase-9 following lysosomal photodamage involves bid cleavage

J. J. Reiners, J. A. Caruso, P. Mathieu, B. Chelladurai, X. M. Yin, D. Kessel

Research output: Contribution to journalArticlepeer-review

267 Scopus citations

Abstract

Photodynamic therapy (PDT) protocols employing lysosomal sensitizers induce apoptosis via a mechanism that causes cytochrome c release prior to loss of mitochondrial membrane potential (ΔΨm). The current study was designed to determine how lysosomal photodamage initiates mitochondrial-mediated apoptosis in murine hepatoma 1c1c7 cells. Fluorescence microscopy demonstrated that the photosensitizer N-aspartyl chlorin e6 (NPe6) localized to the lysosomes. Irradiation of cultures preloaded with NPe6 induced the rapid destruction of lysosomes, and subsequent cleavage/activation of Bid, pro-caspases-9 and -3. Pro-caspase-8 was not activated. Release of cytochrome coccurred at about the time of Bid cleavage and preceded the loss of ΔΨm. Extracts of purified lysosomes catalyzed the in vitro cleavage of cytosolic Bid, but not pro-caspase-3 activation. Pharmacological inhibition of cathepsin B, L and D activities did not suppress Bid cleavage or pro-caspases-9 and -3 activation. These studies demonstrate that photodamaged lysosomes trigger the mitochondrial apoptotic pathway by releasing proteases that activate Bid.

Original languageEnglish (US)
Pages (from-to)934-944
Number of pages11
JournalCell Death and Differentiation
Volume9
Issue number9
DOIs
StatePublished - 2002

Keywords

  • Apoptosis
  • Bid
  • Lysosomes
  • NPe6
  • Photodynamic therapy (PDT)

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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