Journal
JOURNAL OF CELL SCIENCE
Volume 126, Issue 17, Pages 4015-4025Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.129999
Keywords
Apoptosis; TNF alpha; LMP; ROS; Caspase; MOMP; Bax; Bak; Apoptosome; MitoQ
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Funding
- Jose Carreras Foundation, Germany (DJCS) [R 06/09]
- Excellence Initiative, Germany
- Spemann Graduate School of Biology and Medicine [GSC-4]
- l'Agence Nationale de la Recherche [ANR-09-JCJC-0003]
- Institute of Molecular Medicine
- Institute of Biochemistry and Molecular Biology, University of Freiburg, Germany
- Uniklinik Mainz, Germany
- Agence Nationale de la Recherche (ANR) [ANR-09-JCJC-0003] Funding Source: Agence Nationale de la Recherche (ANR)
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When NF-kappa B activation or protein synthesis is inhibited, tumor necrosis factor alpha (TNF alpha) 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 TNF alpha-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 TNF alpha 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 TNF alpha 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 TNF alpha apoptosis signaling.
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