Cited by 1,166Cell death mechanisms and regulationMitochondrial Function and PathologyAutophagy in Disease and Therapy

Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo.

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Zamzami, N, Marchetti, P, Castedo, M, Zanin, C, Vayssière, J L, Petit, P X, Kroemer, G·1995·The Journal of experimental medicine

Abstract

In a number of experimental systems in which lymphocyte depletion was induced by apoptosis-inducing manipulations, no apoptotic morphology and ladder-type DNA fragmentation were detected among freshly isolated peripheral lymphocytes ex vivo. Here we report that one alteration that can be detected among splenocytes stimulated with lymphocyte-depleting doses of dexamethasone (DEX) in vivo is a reduced uptake of 3,3'dihexyloxacarbocyanine iodide (DiOC6[3]), a fluorochrome which incorporates into cells dependent upon their mitochondrial transmembrane potential (delta psi m). In contrast, ex vivo isolated splenocytes still lacked established signs of programmed cell death (PCD):DNA degradation into high or low molecular weight fragments, ultrastructural changes of chromatin arrangement and endoplasmatic reticulum, loss in viability, or accumulation of intracellular peroxides. Moreover, no changes in cell membrane potential could be detected. A reduced delta psi m has been observed in response to different agents inducing lymphoid cell depletion in vivo (superantigen and glucocorticoids [GC]), in mature T and B lymphocytes, as well as their precursors. DEX treatment in vivo, followed by cytofluorometric purification of viable delta psi mlow splenic T cells ex vivo, revealed that this fraction of cells is irreversibly committed to undergoing DNA fragmentation. Immediately after purification neither delta psi mlow, nor delta psi mhigh cells, exhibit detectable DNA fragmentation. However, after short-term culture (37 degrees C, 1 h) delta psi mlow cells show endonucleolysis, followed by cytolysis several hours later. Incubation of delta psi mlow cells in the presence of excess amount of the GC receptor antagonist RU38486 (which displaces DEX from the GC receptor), cytokines that inhibit DEX-induced cell death, or cycloheximide fails to prevent cytolysis. The antioxidant, N-acetylcysteine, as well as linomide, an agent that effectively inhibits DEX or superantigen-induced lymphocyte depletion in vivo, also stabilize the DiOC6(3) uptake. In contrast, the endonuclease inhibitor, aurintricarboxylic acid acts at later stages of apoptosis and only retards the transition from the viable delta psi mlow to the nonviable fraction. Altogether, these data suggest a sequence of PCD-associated events in which a reduction in delta psi m constitutes an obligate irreversible step of ongoing lymphocyte death, preceding other alterations of cellular physiology, and thus allowing for the ex vivo assessment of 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].”

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Authors
Zamzami, N., Marchetti, P., Castedo, M., Zanin, C., Vayssière, J. L., Petit, P. X., & Kroemer, G.
Affiliations
Centre National de la Recherche Scientifique (FR)
Venue
The Journal of experimental medicine
Published
1995-05-01
Volume
181
Issue
5
Pages
1661-1672
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W2098712005
Cited by
1,166
References
49
Citations by year
2026: 4 · 2025: 7 · 2024: 13 · 2023: 10 · 2022: 13 · 2021: 12 · 2020: 10 · 2019: 17 · 2018: 21 · 2017: 29 · 2016: 18 · 2015: 15 · 2014: 27 · 2013: 34 · 2012: 34
FWCI
23.21
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Styrelsen för Internationellt Utvecklingssamarbete
  • Association pour la Recherche sur le Cancer
  • Sidaction
  • Centre National de la Recherche Scientifique
  • LEO Fondet
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
mitochondrial membrane potential, apoptosis, lymphocyte depletion, dexamethasone, glucocorticoids, superantigens, DNA fragmentation, cell lysis, T cells, B cells, DiOC6(3), mifepristone, N-acetylcysteine, linomide, aurintricarboxylic acid, splenocytes, glucocorticoid receptor antagonist, lymphocyte precursors
MeSH terms
Animals, Aurintricarboxylic Acid, Cells, Cultured, Dexamethasone, DNA, Mitochondrial, Female, Lymphocytes, Mice, Inbred BALB C, Mitochondria, Apoptosis, Superantigens, Mice

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