Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores.
Alterations in intracellular Ca(2+) homeostasis and cytochrome c release from mitochondria have been implicated in the regulation of apoptosis, but the relationship between these events remains unclear. Here we report that enforced expression of either Bax or Bak via adenoviral gene delivery results in the accumulation of the proteins in the endoplasmic reticulum (ER) and mitochondria, resulting in early caspase-independent BCL-2-sensitive release of the ER Ca(2+) pool and subsequent Ca(2+) accumulation in mitochondria. The inhibition of ER-to-mitochondrial Ca(2+) transport with a specific inhibitor of mitochondrial Ca(2+) uptake attenuates cytochrome c release and downstream biochemical events associated with apoptosis. Bax and Bak also directly sensitize mitochondria to cytochrome c release induced by immediate emptying of ER Ca(2+) pool. Our results demonstrate that the effects of the "multidomain" proapoptotic BCL-2 family members Bak and Bax involve direct effects on the endoplasmic reticular Ca(2+) pool with subsequent sensitization of mitochondria to calcium-mediated fluxes and cytochrome c release. These effects modulate the kinetics of cytochrome c release and apoptosis.
Nutt
Leta K
LK
Departments of Cancer Biology and Thoracic and Cardiovascular Surgery, Section of Thoracic and Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
Pataer
Abujiang
A
Pahler
Jessica
J
Fang
Bingliang
B
Roth
Jack
J
McConkey
David J
DJ
Swisher
Stephen G
SG
D017209:Apoptosis; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494772:BAK1 protein, human; C494826:BAX protein, human; D003574:Cytochrome c Group; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein