title: Processed caspase-2 can induce mitochondria-mediated apoptosis independently of its enzymatic activity.
abstract: The mechanism by which caspase-2 executes apoptosis remains obscure. Recent findings indicate that caspase-2 is activated early in response to DNA-damaging antineoplastic agents and may be important for the engagement of the mitochondrial apoptotic pathway. We demonstrate here that fully processed caspase-2 stimulates mitochondrial release of cytochrome c and Smac/DIABLO, but not apoptosis-inducing factor (AIF). This event occurs independently of several Bcl-2 family proteins, including Bax, Bak and Bcl-2, and inactivation experiments reveal that the proteolytic activity of caspase-2 is not required for the effect. Further, functional studies of mitochondria indicate that processed caspase-2 stimulates state 4 respiration and decreases the respiratory control ratio as a result of, in large part, an uncoupling effect. Combined, our data suggest that caspase-2 retains a unique ability to engage directly the mitochondrial apoptotic pathway, an effect that requires processing of the zymogen but not the associated catalytic activity.
authors.affiliation: Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: John D
authors.initials: JD
authors.lastname: Robertson
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
authors.forename: Andrey
authors.initials: A
authors.lastname: Kropotov
authors.forename: Helin
authors.initials: H
authors.lastname: Vakifahmetoglu
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: Sten
authors.initials: S
authors.lastname: Orrenius
mesh_terms: D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D053143:Caspase 2; D020169:Caspases / Q000032:analysis / Q000378:metabolism*; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D004789:Enzyme Activation; D005420:Flavoproteins / Q000032:analysis / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000032:analysis / Q000378:metabolism; D010101:Oxygen Consumption; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; D002352:Carrier Proteins; C412403:DIABLO protein, human; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053143:Caspase 2; D020169:Caspases