The Central Executioner of Apoptosis: Multiple Connections between Protease Activation and Mitochondria in Fas/APO-1/CD95- and Ceramide-induced Apoptosis
Santos A. Susin,Naoufal Zamzami,Maria Castedo,Eric Daugas,Hong Gang Wang,Stephan Geley,Florence Fassy,John C. Reed,Guido Kroemer +8 more
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TLDR
A protease activation pathway with the mitochondrial phase of apoptosis regulation is connected, providing a plausible explanation of why Bcl-2 fails to interfere with Fas-triggered apoptosis in most cell types, yet prevents ceramide- and prooxidant-induced apoptosis.cmk.Abstract:
According to current understanding, cytoplasmic events including activation of protease cascades and mitochondrial permeability transition (PT) participate in the control of nuclear apoptosis. However, the relationship between protease activation and PT has remained elusive. When apoptosis is induced by cross-linking of the Fas/APO-1/CD95 receptor, activation of interleukin-1β converting enzyme (ICE; caspase 1) or ICE-like enzymes precedes the disruption of the mitochondrial inner transmembrane potential (ΔΨm). In contrast, cytosolic CPP32/ Yama/Apopain/caspase 3 activation, plasma membrane phosphatidyl serine exposure, and nuclear apoptosis only occur in cells in which the ΔΨm is fully disrupted. Transfection with the cowpox protease inhibitor crmA or culture in the presence of the synthetic ICE-specific inhibitor Ac-YVAD.cmk both prevent the ΔΨm collapse and subsequent apoptosis. Cytosols from anti-Fas–treated human lymphoma cells accumulate an activity that induces PT in isolated mitochondria in vitro and that is neutralized by crmA or Ac-YVAD.cmk. Recombinant purified ICE suffices to cause isolated mitochondria to undergo PT-like large amplitude swelling and to disrupt their ΔΨm. In addition, ICE-treated mitochondria release an apoptosis-inducing factor (AIF) that induces apoptotic changes (chromatin condensation and oligonucleosomal DNA fragmentation) in isolated nuclei in vitro. AIF is a protease (or protease activator) that can be inhibited by the broad spectrum apoptosis inhibitor Z-VAD.fmk and that causes the proteolytical activation of CPP32. Although Bcl-2 is a highly efficient inhibitor of mitochondrial alterations (large amplitude swelling + ΔΨm collapse + release of AIF) induced by prooxidants or cytosols from ceramide-treated cells, it has no effect on the ICE-induced mitochondrial PT and AIF release. These data connect a protease activation pathway with the mitochondrial phase of apoptosis regulation. In addition, they provide a plausible explanation of why Bcl-2 fails to interfere with Fas-triggered apoptosis in most cell types, yet prevents ceramide- and prooxidant-induced apoptosis.read more
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Molecular characterization of mitochondrial apoptosis-inducing factor
Santos A. Susin,Hans K. Lorenzo,Naoufal Zamzami,Isabel Marzo,Bryan E. Snow,Joan Mangion,Etienne Jacotot,Paola Costantini,Markus Loeffler,Nathanael Larochette,David R. Goodlett,Ruedi Aebersold,David P. Siderovski,Josef M. Penninger,Guido Kroemer +14 more
TL;DR: The identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei is reported, indicating that AIF is a mitochondrial effector of apoptotic cell death.
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Bid, a Bcl2 Interacting Protein, Mediates Cytochrome c Release from Mitochondria in Response to Activation of Cell Surface Death Receptors
TL;DR: The purification of a cytosolic protein that induces cytochrome c release from mitochondria in response to caspase-8, the apical caspases activated by cell surface death receptors such as Fas and TNF is reported.
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Two CD95 (APO-1/Fas) signaling pathways
Carsten Scaffidi,Simone Fulda,Anu Srinivasan,Claudia Friesen,Feng Li,Kevin J. Tomaselli,Klaus-Michael Debatin,Peter H. Krammer,Marcus E. Peter +8 more
TL;DR: In the presence of caspase‐3 the amount of active casp enzyme‐8 generated at the DISC determines whether a mitochondria‐independent apoptosis pathway is used (type I cells) or not (type II cells).
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Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.
TL;DR: Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.
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The mitochondrial death/life regulator in apoptosis and necrosis
TL;DR: The acquisition of the biochemical and ultrastructural features of apoptosis critically relies on the liberation of apoptogenic proteases or protease activators from mitochondria.
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