Huai 2013 J Cell Sci: Difference between revisions
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|area=Respiration, Genetic knockout;overexpression | |area=Respiration, Genetic knockout;overexpression | ||
|injuries=Cell death | |||
|organism=Human, Mouse | |organism=Human, Mouse | ||
| | |tissues=HeLa, Fibroblast | ||
|preparations=Intact cells | |preparations=Intact cells | ||
|couplingstates=ROUTINE | |couplingstates=ROUTINE | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
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Latest revision as of 15:34, 9 November 2016
Huai J, VΓΆgtle FN, JΓΆckel L, Li Y, Kiefer T, Ricci JE, Borner C (2013) TNFΞ±-induced lysosomal membrane permeability (LMP) is downstream of MOMP and triggered by caspase-mediated p75 cleavage and ROS formation. J Cell Sci 126:4015-25. |
Huai J, Voegtle FN, Joeckel L, Li Y, Kiefer T, Ricci JE, Borner C (2013) J Cell Sci
Abstract: When NF-ΞΊB activation or protein synthesis is inhibited, tumor necrosis factor alpha (TNFΞ±) can induce apoptosis through Bax- and Bak-mediated mitochondrial outer membrane permeabilization (MOMP) leading to caspase-3 activation. Additionally, previous studies have implicated lysosomal membrane permeability (LMP) and formation of reactive oxygen species (ROS) as early steps of TNFΞ±-induced apoptosis. However, how these two events connect to MOMP and caspase-3 activation has been largely debated. Here, we present the novel finding that LMP induced by the addition of TNFΞ± plus cycloheximide (CHX), the release of lysosomal cathepsins and ROS formation do not occur upstream but downstream of MOMP and require the caspase-3-mediated cleavage of the p75 NDUFS1 subunit of respiratory complex I. Both a caspase non-cleavable p75 mutant and the mitochondrially localized antioxidant MitoQ prevent LMP mediated by TNFΞ± plus CHX and partially interfere with apoptosis induction. Moreover, LMP is completely blocked in cells deficient in both Bax and Bak, Apaf-1, caspase-9 or both caspase-3 and -7. Thus, after MOMP, active caspase-3 exerts a feedback action on complex I to produce ROS. ROS then provoke LMP, cathepsin release and further caspase activation to amplify TNFΞ± apoptosis signaling. β’ Keywords: Apoptosis, Apoptosome, Bak, Bax, Caspase, LMP, MOMP, MitoQ, ROS, TNFΞ±
Labels: MiParea: Respiration, Genetic knockout;overexpression
Stress:Cell death Organism: Human, Mouse Tissue;cell: HeLa, Fibroblast Preparation: Intact cells
Coupling state: ROUTINE
HRR: Oxygraph-2k