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

Research output: Contribution to journalShort survey

309 Citations (Scopus)

Abstract

Mitochondria are frequently the target of injury after stresses leading to necrotic and apoptotic cell death. Inhibition of oxidative phosphorylation progresses to uncoupling when opening of a high conductance permeability transition (PT) pore in the mitochondrial inner membrane abruptly increases the permeability of the mitochondrial inner membrane to solutes of molecular mass up to 1500 Da. Cyclosporin A (CsA) blocks this mitochondrial permeability transition (MPT) and prevents necrotic cell death from oxidative stress, Ca 2+ 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 movement of green-fluorescing calcein into mitochondria and the simultaneous release from mitochondria of red-fluorescing tetramethylrhodamine methylester, a membrane potential-indicating fluorophore. In oxidative stress to hepatocytes induced by tert-butylhydroperoxide, NAD(P)H oxidation, increased mitochondrial Ca 2+ , and mitochondrial generation of reactive oxygen species precede and contribute to onset of the MPT. Confocal microscopy also shows directly that the 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 the MPT has on cellular ATP levels. If ATP levels fall profoundly, necrotic killing ensues. If ATP levels are at least partially maintained, apoptosis follows the MFF. Cellular features of both apoptosis and necrosis frequently occur together after death signals and toxic stresses. A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis) depending on modifying factors such as ATP.

Original languageEnglish (US)
Pages (from-to)305-319
Number of pages15
JournalJournal of Bioenergetics and Biomembranes
Volume31
Issue number4
DOIs
StatePublished - Dec 1 1999

Fingerprint

Permeability
Cell Death
Adenosine Triphosphate
Apoptosis
Mitochondria
Mitochondrial Membranes
Confocal Microscopy
Hepatocytes
Oxidative Stress
Necrosis
tert-Butylhydroperoxide
Poisons
Oxidative Phosphorylation
Ionophores
Wounds and Injuries
Reperfusion Injury
Drug-Related Side Effects and Adverse Reactions
Fluorescence Microscopy
NAD
Membrane Potentials

Keywords

  • Apoptosis
  • Confocal microscopy
  • Cyclosporin A
  • Cytochrome c
  • Ischemia/reperfusion
  • Mitochondrial permeability transition
  • Necrapoptosis
  • Necrosis
  • Oxidative stress

Cite this

Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death. / Lemasters, John J.; Qian, Ting; Bradham, Cynthia A.; Brenner, David A.; Cascio, Wayne E.; Trost, Lawrence C.; Nishimura, Yoshiya; Nieminen, Anna Liisa; Herman, Brian.

In: Journal of Bioenergetics and Biomembranes, Vol. 31, No. 4, 01.12.1999, p. 305-319.

Research output: Contribution to journalShort survey

Lemasters, JJ, Qian, T, Bradham, CA, Brenner, DA, Cascio, WE, Trost, LC, Nishimura, Y, Nieminen, AL & Herman, B 1999, 'Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death', Journal of Bioenergetics and Biomembranes, vol. 31, no. 4, pp. 305-319. https://doi.org/10.1023/A:1005419617371
Lemasters, John J. ; Qian, Ting ; Bradham, Cynthia A. ; Brenner, David A. ; Cascio, Wayne E. ; Trost, Lawrence C. ; Nishimura, Yoshiya ; Nieminen, Anna Liisa ; Herman, Brian. / Mitochondrial dysfunction in the pathogenesis of necrotic and apoptotic cell death. In: Journal of Bioenergetics and Biomembranes. 1999 ; Vol. 31, No. 4. pp. 305-319.
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AU - Cascio, Wayne E.

AU - Trost, Lawrence C.

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AU - Nieminen, Anna Liisa

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N2 - Mitochondria are frequently the target of injury after stresses leading to necrotic and apoptotic cell death. Inhibition of oxidative phosphorylation progresses to uncoupling when opening of a high conductance permeability transition (PT) pore in the mitochondrial inner membrane abruptly increases the permeability of the mitochondrial inner membrane to solutes of molecular mass up to 1500 Da. Cyclosporin A (CsA) blocks this mitochondrial permeability transition (MPT) and prevents necrotic cell death from oxidative stress, Ca 2+ 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 movement of green-fluorescing calcein into mitochondria and the simultaneous release from mitochondria of red-fluorescing tetramethylrhodamine methylester, a membrane potential-indicating fluorophore. In oxidative stress to hepatocytes induced by tert-butylhydroperoxide, NAD(P)H oxidation, increased mitochondrial Ca 2+ , and mitochondrial generation of reactive oxygen species precede and contribute to onset of the MPT. Confocal microscopy also shows directly that the 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 the MPT has on cellular ATP levels. If ATP levels fall profoundly, necrotic killing ensues. If ATP levels are at least partially maintained, apoptosis follows the MFF. Cellular features of both apoptosis and necrosis frequently occur together after death signals and toxic stresses. A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis) depending on modifying factors such as ATP.

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KW - Oxidative stress

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