VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release

Muniswamy Madesh, György Hajnóczky

Producción científica: Articlerevisión exhaustiva

466 Citas (Scopus)

Resumen

Enhanced formation of reactive oxygen species (ROS), superoxide (O2·-), and hydrogen peroxide (H2O2) may result in either apoptosis or other forms of cell death. Here, we studied the mechanisms underlying activation of the apoptotic machinery by ROS. Exposure of permeabilized HepG2 cells to O2·- elicited rapid and massive cytochrome c release (CCR), whereas H2O2 failed to induce any release. Both O2·- and H2O2 promoted activation of the mitochondrial permeability transition pore by Ca2+, but Ca2+-dependent pore opening was not required for O2·--induced CCR. Furthermore, O2·- alone evoked CCR without damage of the inner mitochondrial membrane barrier, as mitochondrial membrane potential was sustained in the presence of extramitochondrial ATP. Strikingly, pretreatment of the cells with drugs or an antibody, which block the voltage-dependent anion channel (VDAC), prevented O2·--induced CCR. Furthermore, VDAC-reconstituted liposomes permeated cytochrome c after O2·- exposure, and this release was prevented by VDAC blocker. The proapoptotic protein, Bak, was not detected in HepG2 cells and O2·--induced CCR did not depend on Bax translocation to mitochondria. O2·--induced CCR was followed by caspase activation and execution of apoptosis. Thus, O2·- triggers apoptosis via VDAC-dependent permeabilization of the mitochondrial outer membrane without apparent contribution of proapoptotic Bcl-2 family proteins.

Idioma originalEnglish (US)
Páginas (desde-hasta)1003-1015
Número de páginas13
PublicaciónJournal of Cell Biology
Volumen155
N.º6
DOI
EstadoPublished - dic 10 2001
Publicado de forma externa

ASJC Scopus subject areas

  • Cell Biology

Huella

Profundice en los temas de investigación de 'VDAC-dependent permeabilization of the outer mitochondrial membrane by superoxide induces rapid and massive cytochrome c release'. En conjunto forman una huella única.

Citar esto