tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak.
TNFR1/Fas engagement results in the cleavage of cytosolic Bid to truncated Bid (tBid), which translocates to mitochondria. We demonstrate that recombinant tBid induces in vitro immediate destabilization of the mitochondrial bioenergetic homeostasis. These alterations result in mild uncoupling of mitochondrial state-4 respiration, associated with an inhibition the adenosine diphosphate (ADP)-stimulated respiration and phosphorylation rate. tBid disruption of mitochondrial homeostasis was inhibited in mitochondria overexpressing Bcl-2 and Bcl-XL. The inhibition of state-3 respiration is mediated by the reorganization of cardiolipin within the mitochondrial membranes, which indirectly affects the activity of the ADP/ATP translocator. Cardiolipin-deficient yeast mitochondria did not exhibit any respiratory inhibition by tBid, proving the absolute requirement for cardiolipin for tBid binding and activity. In contrast, the wild-type yeast mitochondria underwent a similar inhibition of ADP-stimulated respiration associated with reduced ATP synthesis. These events suggest that mitochondrial lipids rather than proteins are the key determinants of tBid-induced destabilization of mitochondrial bioenergetics.
Gonzalvez
F
F
Département de Génétique, Développement et Pathologies Moléculaires, Institut Cochin, INSERM U567/CNRS UMR 8104, 24, rue du Faubourg Saint-Jacques, 750014 Paris, France.
Pariselli
F
F
Dupaigne
P
P
Budihardjo
I
I
Lutter
M
M
Antonsson
B
B
Diolez
P
P
Manon
S
S
Martinou
J-C
JC
Goubern
M
M
Wang
X
X
Bernard
S
S
Petit
P X
PX
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein; D002308:Cardiolipins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; C494815:Bid protein, mouse; D002308:Cardiolipins; D002352:Carrier Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000244:Adenosine Diphosphate; D045304:Cytochromes c