Bax and heart mitochondria: uncoupling and inhibition of respiration without permeability transition.
The effects of Bax (full-length, FL, and C-terminal truncated, DeltaC) on respiration rate, membrane potential, MgATPase activity and kinetics of regulation of respiration were studied in isolated rat heart mitochondria and permeabilized cardiomyocytes. The results showed that while both Bax-FL and Bax-DeltaC permeabilized the outer mitochondrial membrane, released cytochrome c and reduced the respiration rate, the latter could be fully restored by exogenous cytochrome c only in the case of Bax-DeltaC, but not in presence of Bax-FL. In addition, Bax-FL but not Bax-DeltaC increased the MgATPase activity, and their effects on the mitochondrial membrane potential were quantitatively different. None of these effects was sensitive to cyclosporin A (CsA). It is concluded that Bax-FL affects both the outer and the inner mitochondrial membranes by: (1) opening large pores in the outer membrane; (2) inhibiting some segments of the respiratory chain in the inner membrane; and (3) uncoupling the inner mitochondrial membrane by increasing proton leak without opening the permeability transition pore (PTP).
Appaix
Florence
F
University of Joseph Fourier, B.P. 35 X, 38041 Cedex 9, Grenoble, France.
Guerrero
Karen
K
Rampal
David
D
Izikki
Mohamed
M
Kaambre
Tuuli
T
Sikk
Peeter
P
Brdiczka
Dieter
D
Riva-Lavieille
Catherine
C
Olivares
Jose
J
Longuet
Michel
M
Antonsson
Bruno
B
Saks
Valdur A
VA
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000378:metabolism; D002458:Cell Fractionation; D019069:Cell Respiration / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology*; D008929:Mitochondria, Heart / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017208:Rats, Wistar; D014475:Uncoupling Agents / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014475:Uncoupling Agents; D051028:bcl-2-Associated X Protein; D000244:Adenosine Diphosphate; D017301:Ca(2+) Mg(2+)-ATPase; D010100:Oxygen