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Cited by 1,567Cell death mechanisms and regulationMitochondrial Function and PathologyAutophagy in Disease and Therapy

Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death.

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Zamzami, N, Marchetti, P, Castedo, M, Decaudin, D, Macho, A, Hirsch, T, Susin, S A, Petit, P X +2 more·1995·The Journal of experimental medicine
DOI 10.1084/jem.182.2.367PMC PMC2192111
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Abstract

Programmed cell death (PCD) is a physiological process commonly defined by alterations in nuclear morphology (apoptosis) and/or characteristic stepwise degradation of chromosomal DNA occurring before cytolysis. However, determined characteristics of PCD such as loss in mitochondrial reductase activity or cytolysis can be induced in enucleated cells, indicating cytoplasmic PCD control. Here we report a sequential disregulation of mitochondrial function that precedes cell shrinkage and nuclear fragmentation. A first cyclosporin A-inhibitable step of ongoing PCD is characterized by a reduction of mitochondrial transmembrane potential, as determined by specific fluorochromes (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine++ + iodide; 3,3'dihexyloxacarbocyanine iodide). Cytofluorometrically purified cells with reduced mitochondrial transmembrane potential are initially incapable of oxidizing hydroethidine (HE) into ethidium. Upon short-term in vitro culture, such cells acquire the capacity of HE oxidation, thus revealing a second step of PCD marked by mitochondrial generation of reactive oxygen species (ROS). This step can be selectively inhibited by rotenone and ruthenium red yet is not affected by cyclosporin A. Finally, cells reduce their volume, a step that is delayed by radical scavengers, indicating the implication of ROS in the apoptotic process. This sequence of alterations accompanying early PCD is found in very different models of apoptosis induction: glucocorticoid-induced death of lymphocytes, activation-induced PCD of T cell hybridomas, and tumor necrosis factor-induced death of U937 cells. Transfection with the antiapoptotic protooncogene Bcl-2 simultaneously inhibits mitochondrial alterations and apoptotic cell death triggered by steroids or ceramide. In vivo injection of fluorochromes such as 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide; 3,3'dihexyloxacarbocyanine iodide; or HE allows for the detection of cells that are programmed for death but still lack nuclear DNA fragmentation. In particular, assessment of mitochondrial ROS generation provides an accurate picture of PCD-mediated lymphocyte depletion. In conclusion, alterations of mitochondrial function constitute an important feature of early PCD.

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  • MOMP eventually leads to the dissipation of the mitochondrial transmembrane potential (Δψm)-mostly as a consequence of the respiratory impairment imposed by the loss of CYCS-and hence to the cessation of Δψm-dependent mitochondrial functions (including ATP synthesis and some forms of protein import).

    “Of note, MOMP eventually leads to the dissipation of the mitochondrial transmembrane potential (Δψm)—mostly as a consequence of the respiratory impairment imposed by the loss of CYCS—and hence to the cessation of Δψm-dependent mitochondrial functions (including ATP synthesis and some forms of protein import) [200–203].”

    From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [202]

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Authors
Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S. A., Petit, P. X., Mignotte, B., & Kroemer, G.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Centre National de la Recherche Scientifique, Unité Propre de Recherche 420, Villejuif, France.
ORCID
Venue
The Journal of experimental medicine
Publisher
Rockefeller University Press
Published
1995-08-01
Volume
182
Issue
2
Pages
367-377
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.182.2.367
PMC
PMC2192111
OpenAlex
W2101575450
Cited by
1,567
References
72
Citations by year
2026: 9 · 2025: 14 · 2024: 17 · 2023: 15 · 2022: 23 · 2021: 23 · 2020: 27 · 2019: 38 · 2018: 45 · 2017: 52 · 2016: 33 · 2015: 39 · 2014: 61 · 2013: 39 · 2012: 32
FWCI
25.77
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
programmed cell death, apoptosis, mitochondrial membrane potential, reactive oxygen species, mitochondrial dysfunction, cyclosporine, rotenone, ruthenium red, Bcl-2, ceramide, lymphocyte depletion
MeSH terms
Animals, Antioxidants, Cell Line, Cell Membrane, Dexamethasone, Female, Humans, Intracellular Membranes, Lymphocytes, Membrane Potentials, Mice, Inbred BALB C, Mitochondria, Spleen, Time Factors, Apoptosis, Reactive Oxygen Species, Mice, In Vitro Techniques

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