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Mitochondrial Dysfunction in the Pathogenesis of Necrotic and Apoptotic Cell Death

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Abstract

Mitochondria are frequently the target of injury after stresses leading to necrotic and apoptoticcell death. Inhibition of oxidative phosphorylation progresses to uncoupling when opening ofa high conductance permeability transition (PT) pore in the mitochondrial inner membraneabruptly increases the permeability of the mitochondrial inner membrane to solutes of molecularmass up to 1500 Da. Cyclosporin A (CsA) blocks this mitochondrial permeability transition(MPT) and prevents necrotic cell death from oxidative stress, Ca2+ ionophore toxicity,Reye-related drug toxicity, pH-dependent ischemia/reperfusion injury, and other models of cell injury.Confocal fluorescence microscopy directly visualizes onset of the MPT from the movementof green-fluorescing calcein into mitochondria and the simultaneous release from mitochondriaof red-fluorescing tetramethylrhodamine methylester, a membrane potential-indicatingfluorophore. In oxidative stress to hepatocytes induced by tert-butylhydroperoxide, NAD(P)Hoxidation, increased mitochondrial Ca2+, and mitochondrial generation of reactive oxygen speciesprecede and contribute to onset of the MPT. Confocal microscopy also shows directly thatthe MPT is a critical event in apoptosis of hepatocytes induced by tumor necrosis factor-α.Progression to necrotic and apoptotic cell killing depends, at least in part, on the effect theMPT has on cellular ATP levels. If ATP levels fall profoundly, necrotic killing ensues. If ATPlevels are at least partially maintained, apoptosis follows the MPT. Cellular features of bothapoptosis and necrosis frequently occur together after death signals and toxic stresses. A newterm, necrapoptosis, describes such death processes that begin with a common stress or deathsignal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmedcellular resorption (apoptosis) depending on modifying factors such as ATP.

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Authors and Affiliations

  1. Department of Cell Biology and Anatomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27799-7090.

    John J. Lemasters & Ting Qian

  2. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27799-7090

    Cynthia A. Bradham, David A. Brenner & Wayne E. Cascio

  3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27799-7090

    Cynthia A. Bradham & David A. Brenner

  4. Department of Toxicology, Triangle Pharmaceuticals, Durham, North Carolina, 27707

    Lawrence C. Trost

  5. Division of Gastroenterology, Osaka National Hospital, Osaka, Japan

    Yoshiya Nishimura

  6. Department of Anatomy, Case Western University, Cleveland, Ohio, 44106

    Anna-Liisa Nieminen

  7. Department of Cellular and Structural Biology, The University of Texas Health Center at San Antonio, San Antonio, Texas, 78285

    Brian Herman

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Lemasters, J.J., Qian, T., Bradham, C.A. et al. Mitochondrial Dysfunction in the Pathogenesis of Necrotic and Apoptotic Cell Death. J Bioenerg Biomembr 31, 305–319 (1999). https://doi.org/10.1023/A:1005419617371

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