Journal of Bioenergetics and Biomembranes

, Volume 31, Issue 4, pp 305–319

Mitochondrial Dysfunction in the Pathogenesis of Necrotic and Apoptotic Cell Death

  • John J. Lemasters
  • Ting Qian
  • Cynthia A. Bradham
  • David A. Brenner
  • Wayne E. Cascio
  • Lawrence C. Trost
  • Yoshiya Nishimura
  • Anna-Liisa Nieminen
  • Brian Herman
Article

DOI: 10.1023/A:1005419617371

Cite this article as:
Lemasters, J.J., Qian, T., Bradham, C.A. et al. J Bioenerg Biomembr (1999) 31: 305. doi:10.1023/A:1005419617371

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.

Apoptosisconfocal microscopycyclosporin Acytochrome c;ischemia/reperfusionmitochondrial permeability transitionnecrapoptosisnecrosisoxidative stress

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • John J. Lemasters
    • 1
  • Ting Qian
    • 1
  • Cynthia A. Bradham
    • 2
    • 3
  • David A. Brenner
    • 2
    • 3
  • Wayne E. Cascio
    • 2
  • Lawrence C. Trost
    • 4
  • Yoshiya Nishimura
    • 5
  • Anna-Liisa Nieminen
    • 6
  • Brian Herman
    • 7
  1. 1.Department of Cell Biology and AnatomyUniversity of North Carolina at Chapel HillChapel Hill
  2. 2.Department of MedicineUniversity of North Carolina at Chapel HillChapel Hill
  3. 3.Department of Biochemistry and BiophysicsUniversity of North Carolina at Chapel HillChapel Hill
  4. 4.Department of ToxicologyTriangle PharmaceuticalsDurham
  5. 5.Division of GastroenterologyOsaka National HospitalOsakaJapan
  6. 6.Department of AnatomyCase Western UniversityCleveland
  7. 7.Department of Cellular and Structural BiologyThe University of Texas Health Center at San AntonioSan Antonio