Abstract:
BACKGROUND & AIMS:Nuclear factor kappaB (NF-kappaB) is the master regulator of tumor necrosis factor (TNF) susceptibility. Although mitochondrial glutathione (mGSH) depletion was shown to sensitize hepatocytes to TNF despite NF-kappaB activation, the mechanisms involved, particularly the role of Bax oligomerization and mitochondrial outer membrane (MOM) permeabilization, 2 critical steps in cell death, remained unexplored. METHODS:TNF signaling at the premitochondrial and mitochondrial levels was analyzed in primary mouse hepatocytes with or without mGSH depletion. RESULTS:Unexpectedly, we observed that TNF activates caspase-8 independently of NF-kappaB inactivation, causing Bid cleavage and mitochondrial Bax oligomerization. However, their predicted consequences on MOM permeabilization, cytochrome c release, caspase-3 activation, and hepatocellular death occurred only on mGSH depletion. These events were preceded by stimulated mitochondrial reactive oxygen species that predominantly oxidized cardiolipin, changes not observed in acidic sphingomyelinase (ASMase)(-/-) hepatocytes. Oxidized cardiolipin potentiated oligomerized Bax-induced MOM-like liposome permeabilization by restructuring the lipid bilayer, without effect on membrane Bax insertion or oligomerization. ASMase(-/-) mice with mGSH depletion by cholesterol loading were resistant to TNF-induced liver injury in vivo. CONCLUSIONS:Thus, MOM-localized oligomeric Bax is not sufficient for TNF-induced MOM permeabilization and cell death requiring mGSH-controlled ASMase-mediated mitochondrial membrane remodeling by oxidized cardiolipin generation.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Marí M,Colell A,Morales A,Caballero F,Moles A,Fernández A,Terrones O,Basañez G,Antonsson B,García-Ruiz C,Fernández-Checa JCdoi
10.1053/j.gastro.2008.01.073subject
Has Abstractpub_date
2008-05-01 00:00:00pages
1507-20issue
5eissn
0016-5085issn
1528-0012pii
S0016-5085(08)00179-0journal_volume
134pub_type
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