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Cited by 1,387Mitochondrial Function and PathologyCell death mechanisms and regulationCardiac Ischemia and Reperfusion

The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy

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Lemasters, John J., Nieminen, Anna-Liisa, Qian, Ting, Trost, Lawrence C., Elmore, Steven P., Nishimura, Yoshiya, Crowe, Ruth A., Cascio, Wayne E. +3 more·1998·Biochimica et Biophysica Acta (BBA) - Bioenergetics
DOI 10.1016/s0005-2728(98)00112-1
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Abstract

Using confocal microscopy, onset of the mitochondrial permeability transition (MPT) in individual mitochondria within living cells can be visualized by the redistribution of the cytosolic fluorophore, calcein, into mitochondria. Simultaneously, mitochondria release membrane potential-indicating fluorophores like tetramethylrhodamine methylester. The MPT occurs in several forms of necrotic cell death, including oxidative stress, pH-dependent ischemia/reperfusion injury and Ca2+ ionophore toxicity. Cyclosporin A (CsA) and trifluoperazine block the MPT in these models and prevent cell killing, showing that the MPT is a causative factor in necrotic cell death. During oxidative injury induced by t-butylhydroperoxide, onset of the MPT is preceded by pyridine nucleotide oxidation, mitochondrial generation of reactive oxygen species, and an increase of mitochondrial free Ca2+, all changes that promote the MPT. During tissue ischemia, acidosis develops. Because of acidotic pH, anoxic cell death is substantially delayed. However, when pH is restored to normal after reperfusion (reoxygenation at pH 7.4), cell death occurs rapidly (pH paradox). This killing is caused by pH-dependent onset of the MPT, which is blocked by reperfusion at acidotic pH or with CsA. In isolated mitochondria, toxicants causing Reye's syndrome, such as salicylate and valproate, induce the MPT. Similarly, salicylate induces a CsA-sensitive MPT and killing of cultured hepatocytes. These in vitro findings suggest that the MPT is the pathophysiological mechanism underlying Reye's syndrome in vivo. Kroemer and coworkers proposed that the MPT is a critical event in the progression of apoptotic cell death. Using confocal microscopy, the MPT can be directly documented during tumor necrosis factor-alpha induced apoptosis in hepatocytes. CsA blocks this MPT and prevents apoptosis. The MPT does not occur uniformly during apoptosis. Initially, a small proportion of mitochondria undergo the MPT, which increases to nearly 100% over 1-3 h. A technique based on fluorescence resonance energy transfer can selectively reveal mitochondrial depolarization. After nutrient deprivation, a small fraction of mitochondria spontaneously depolarize and enter an acidic lysosomal compartment, suggesting that the MPT precedes the normal process of mitochondrial autophagy. A model is proposed in which onset of the MPT to increasing numbers of mitochondria within a cell leads progressively to autophagy, apoptosis and necrotic cell death.

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  • Recognition and removal of damaged mitochondria by mitophagy can avoid apoptotic changes by preventing release of mitochondrial apoptogens such as cytochrome c or AIF.

    “Recognition and removal of these mitochondria by mitophagy can avoid apoptotic changes by preventing the release of mitochondrial apoptogens, such as cytochrome c or AIF (242).”

    From Redox regulation of mitochondrial function (2012) · cites this paper as [242]

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  1. H. Sies, Nicotinamide nucleotide compartmentation, in: H. Sies (Ed.), Metabolic Compartmentation, Academic Press, London, 1982, pp. 205^231.

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Authors
Lemasters, J. J., Nieminen, A.-L., Qian, T., Trost, L. C., Elmore, S. P., Nishimura, Y., Crowe, R. A., Cascio, W. E., Bradham, C. A., Brenner, D. A., & Herman, B.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Case Western Reserve University (US)
Corresponding author
Lemasters, John J.
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - Bioenergetics
Publisher
Elsevier BV
Published
1998-08
Volume
1366
Issue
1-2
Pages
177-196
ISSN
0005-2728 (ISSN-L)
DOI
10.1016/s0005-2728(98)00112-1
OpenAlex
W1996907401
Cited by
1,387
References
135
Citations by year
2026: 8 · 2025: 13 · 2024: 14 · 2023: 23 · 2022: 22 · 2021: 25 · 2020: 36 · 2019: 38 · 2018: 36 · 2017: 45 · 2016: 58 · 2015: 43 · 2014: 60 · 2013: 46 · 2012: 50
FWCI
26.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ag013637-05, DK37034, AG07218)
  • National Institute on Aging (AG13637, AG 07218)
  • Office of Naval Research (N00014)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 37034)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
Keywords
mitochondrial permeability transition, necrosis, apoptosis, autophagy, cyclosporine, trifluoperazine, oxidative stress, ischemia-reperfusion injury, Reye's syndrome, salicylates, valproic acid, hepatocytes, TNF-α, mitochondrial depolarization, mitophagy, lysosomal acidification
MeSH terms
Calcimycin, Animals, Autophagy, Calcium, Cells, Cultured, Fluoresceins, Hydrogen-Ion Concentration, Mitochondria, Mitochondria, Liver, Necrosis, Permeability, Peroxides, Rhodamines, Superoxides, Cyclosporine, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Microscopy, Confocal, tert-Butylhydroperoxide

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