cRel induces mitochondrial alterations in correlation with proliferation arrest.
We have previously shown that overexpressing cRel, a transcription factor of the Rel/NF-kappa B family, concomitantly inhibits proliferation of HeLa cells and makes them resistant against TNF alpha-induced apoptosis. Both effects rely on the upregulation of the manganese superoxide dismutase (MnSOD), a mitochondrial enzyme that converts O(2)(*-) in H(2)O(2). Here we describe additional alterations induced by cRel, namely mitochondrial clustering and accumulation of dense dark granules near the nucleus. These changes preferentially occur in cells that display a sustained cRel expression in the nucleus and that are cell-cycle arrested. As the cell-cycle arrest, these changes are reproduced by directly overexpressing MnSOD or by treating cells with H(2)O(2), suggesting they are due to MnSOD induction and ensuing H(2)O(2) accumulation. We propose that mitochondria cluster because they are damaged by the H(2)O(2) they overproduce. They would then be autophagocytosed and degraded in secondary lysosomes. In support of this scenario, we documented the occurrence of oxidative damage and the presence of lysosomes in the area of mitochondrial clustering. In addition, we identified the dense dark granules as lipofuscin, based on their autofluorescence. Lipofuscin could directly originate from the mitochondrial degradation products that would aggregate and become indigestible because of the presence of H(2)O(2) in the secondary lysosomes. Altogether, our findings show that cRel overexpression in HeLa cells creates, via the induction of MnSOD, an oxidative injury that culminates in mitochondrial degeneration, proliferation blockage, and resistance against TNF alpha-induced apoptosis.
Bernard
D
D
FRE 2353 CNRS/Institut Pasteur de Lille/Université Lille 2, Institut de Biologie de Lille, Lille, France.
Slomianny
C
C
Vandenbunder
B
B
Abbadie
C
C
D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D006367:HeLa Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008062:Lipofuscin / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D010084:Oxidation-Reduction; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics* / Q000502:physiology
D008062:Lipofuscin; D020569:Proto-Oncogene Proteins c-rel; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase