Confocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death

John J. Lemasters, Ting Qian, Lawrence C. Trost, Brian Herman, Wayne E. Cascio, Cynthia A. Bradham, David A. Brenner, Anna Liisa Nieminen

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Opening of a high-conductance pore in the mitochondrial inner membrane induces onset of the mitochondrial permeability transition (mPT). Cyclosporin A and trifluoperazine inhibit this pore and block necrotic cell death in oxidative stress, Ca2+ ionophore toxicity, Reye-related drug toxicity, pH-dependent ischaemia/reperfusion injury and other models of cell injury. Confocal fluorescence microscopy directly visualizes the increased mitochondrial membrane permeability of the mPT from the movement of calcein from the cytosol into the matrix space. Pyridine nucleotide oxidation, increased mitochondrial Ca2+ and mitochondrial generation of reactive oxygen species (ROS) all contribute to the onset of the mPT in situ. Confocal microscopy also shows directly that the mPT is a critical link in apoptotic signalling by tumour necrosis factor-α at a point downstream of caspase 8 and upstream of caspase 3. Cyclosporin A blocks this mPT, preventing release of pro-apoptotic cytochrome c from mitochondria and subsequent apoptotic cell killing. Progression to necrosis or apoptosis after the mPT depends on the availability of ATP, which blocks necrosis but promotes the apoptotic programme. Given the pathophysiological importance of the mPT, development of agents to modulate the mPT represents an important new goal for pharmaceutical drug discovery.

Original languageEnglish (US)
Pages (from-to)205-222
Number of pages18
JournalBiochemical Society symposium
Volume66
DOIs
StatePublished - 1999

Fingerprint Dive into the research topics of 'Confocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death'. Together they form a unique fingerprint.

  • Cite this

    Lemasters, J. J., Qian, T., Trost, L. C., Herman, B., Cascio, W. E., Bradham, C. A., Brenner, D. A., & Nieminen, A. L. (1999). Confocal microscopy of the mitochondrial permeability transition in necrotic and apoptotic cell death. Biochemical Society symposium, 66, 205-222. https://doi.org/10.1042/bss0660205