The mitochondrial apoptosis-induced channel (MAC) corresponds to a late apoptotic event.
We have investigated the mechanism responsible for mitochondria permeabilization occurring during cell apoptosis. We have developed an in vivo model of apoptotic rat liver. Mitochondria appeared as an homogenous population in control liver. On the contrary, mitochondria varied in size, morphology, and the matrical density in apoptotic liver. Mitochondria were purified from control and apoptotic livers. In control conditions, a single mitochondrial population was identified; whereas three populations of mitochondria were purified from apoptotic liver. Our data show that these apoptotic populations correspond to early, intermediate, and late apoptotic mitochondria, which are characterized by an increasing extent of permeabilization of their outer membrane and a gradual enrichment in oligomerized Bax protein. Remarkably, a new ionic channel was observed in apoptotic but not in control mitochondria. The biophysical and pharmacological properties of this channel are in good agreement with those reported for a previously described mitochondrial apoptosis-induced channel (MAC) (Pavlov, E. V., Priault, M., Pietkiewicz, D., Cheng, E. H., Antonsson, B., Manon, S., Korsmeyer, S. J., Mannella, C. A., and Kinnally, K. W. (2001) J. Cell Biol. 155, 725-731). However, MAC activity was only observed in the late apoptotic mitochondrial population. Thus, our study establishes that MAC activity is related to the overall apoptotic process but corresponds to a late event.
Guihard
Gilles
G
INSERM UMR 601, Département de Recherche en Cancérologie (DRC), Equipe labellisée Ligue contre le cancer, 9 quai Moncousu, 44035 Nantes Cedex, France. gilles.guihard@nantes.inserm.fr
Bellot
Gregory
G
Moreau
Carole
C
Pradal
Gilbert
G
Ferry
Nicolas
N
Thomy
Raphael
R
Fichet
Paulette
P
Meflah
Khaled
K
Vallette
François Marie
FM
D000818:Animals; D000838:Anions; D017209:Apoptosis; D055592:Biophysical Phenomena; D001703:Biophysics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D015151:Immunoblotting; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000737:chemistry* / Q000502:physiology*; D007477:Ions; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000502:physiology*; D010539:Permeability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D051028:bcl-2-Associated X Protein
D000838:Anions; C494828:Bax protein, rat; D007473:Ion Channels; D007477:Ions; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases