کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6096913 | 1209877 | 2008 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanism of Mitochondrial Glutathione-Dependent Hepatocellular Susceptibility to TNF Despite NF-κB Activation
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کلمات کلیدی
TNFJnkMrOSASMaseMnSODmGSHFLIPIAPNF-κBc-Jun N-terminal kinase - C-Jun N-terminal kinaseSmall interfering RNA - RNA تداخل کوچکsiRNA - siRNAacidic sphingomyelinase - اسفنجومیلیناز اسیدیlarge unilamellar vesicle - بزرگ کیسه بیضهtBid - تخم ریزی کردنtruncated Bid - تضعیف مزایدهmanganese superoxide dismutase - سوپر اکسید دیسموتاز منگنزmitochondrial outer membrane - غشای بیرونی میتوکندریtumor necrosis factor - فاکتور نکروز تومورnuclear factor κB - فاکتور هسته ای κBLUV - لووMoM - مامانinhibitor of apoptosis - مهارکننده آپوپتوزmitochondrial glutathione - گلوتاتیون میتوکندریmitochondrial reactive oxygen species - گونه های اکسیژن واکنش پذیر میتوکندری
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
بیماریهای گوارشی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Background & Aims: Nuclear factor κB (NF-κB) is the master regulator of tumor necrosis factor (TNF) susceptibility. Although mitochondrial glutathione (mGSH) depletion was shown to sensitize hepatocytes to TNF despite NF-κB 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-κB 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)â/â hepatocytes. Oxidized cardiolipin potentiated oligomerized Bax-induced MOM-like liposome permeabilization by restructuring the lipid bilayer, without effect on membrane Bax insertion or oligomerization. ASMaseâ/â 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Gastroenterology - Volume 134, Issue 5, May 2008, Pages 1507-1520
Journal: Gastroenterology - Volume 134, Issue 5, May 2008, Pages 1507-1520
نویسندگان
Montserrat MarÃ, Anna Colell, Albert Morales, Francisco Caballero, Anna Moles, Anna Fernández, Oihana Terrones, Gorka Basañez, Bruno Antonsson, Carmen GarcÃa-Ruiz, José C. Fernández-Checa,