Disruption of the outer mitochondrial membrane as a result of large amplitude swelling: the impact of irreversible permeability transition

FEBS Letters

Petit, Patrice X¹  Goubern, Marc²  Susin, Santos A¹  Diolez, Philippe³  Zamzami, Naoufal¹  Kroemer, Guido¹ 

[1] CNRS UPR420, Génétique Moléculaire et Biologie du Développement 19, rue Guy-Moquet, P.O. Box 8, F-94801 Villejuif, France;INRA (EPHE) Centre de Recherche de Jouy-en-Josas, Domaine de Vilvert, F-78352 Jouy-en-Josas, France;Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS/Bordeaux 2, 146 rue Léo Saignat, F-33076 Bordeaux, France

关键词: Cytochrome c;    Mitochondrial transmembrane potential;    Permeability transition;    Swelling;    Outer membrane disruption;    Hypoploidy;    AIF;    apoptosis inducing factor;    Cyt c;    cytochrome c;    DiOC6(3);    3;    3′-dihexyloxacarbocyanine iodide;    mClCCP;    carbonyl cyanide m-chlorophenylhydrazone;    PT;    permeability transition;    ΔΨm;    mitochondrial membrane potential;    EGTA;    ethylene glycol-bis(β-aminoethyl ether) N;    N′;    N″-tetraacetic acid;    FSpeak;    forward angle light scatter peak;    PCD;    programmed cell death;    tert-BHP;    tert-butyl hydroperoxide;    TPP+;    tetraphenylphosphonium;   

DOI  :  10.1016/S0014-5793(98)00318-4

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Upon induction of permeability transition with different agents (Ca²⁺, tert-butyl hydroperoxide, atractyloside), mouse hepatocyte mitochondria manifest a disruption of outer membrane integrity leading to the release of cytochrome c and apoptosis-inducing factor (AIF), two proteins which are involved in programmed cell death (apoptosis). Chelation of Ca²⁺ shortly (within 2 min) after its addition to isolated mitochondria reestablished the mitochondrial transmembrane potential (ΔΨ_m), prevented induction of large amplitude swelling and release of both cytochrome c and AIF. In contrast, late Ca²⁺ chelation (10 min after addition of Ca²⁺) failed to affect these parameters. Cytochrome c appears to be released through a mechanically damaged outer mitochondrial membrane rather than via a specific release mechanism. These findings clarify the mechanisms through which irreversible permeability transition occurs with subsequent large amplitude swelling culminating in the release of intermembrane proteins from mitochondria. Moreover, they confirm the hypothesis formulated by Skulachev [FEBS Lett. 397 (1996) 7–10 and Q. Rev. Biophys. 29 (1996) 169–202] linking permeability transition to activation of the apoptogenic catabolic enzymes.

【 授权许可】

Unknown