title: Induction of the intrinsic apoptosis pathway in insulin-secreting cells is dependent on oxidative damage of mitochondria but independent of caspase-12 activation.
abstract: Pro-inflammatory cytokine-mediated beta cell apoptosis is activated through multiple signaling pathways involving mitochondria and endoplasmic reticulum. Activation of organelle-specific caspases has been implicated in the progression and execution of cell death. This study was therefore performed to elucidate the effects of pro-inflammatory cytokines on a possible cross-talk between the compartment-specific caspases 9 and 12 and their differential contribution to beta cell apoptosis. Moreover, the occurrence of ROS-mediated mitochondrial damage in response to beta cell toxic cytokines has been quantified. ER-specific caspase-12 was strongly activated in response to pro-inflammatory cytokines; however, its inhibition did not abolish cytokine-induced mitochondrial caspase-9 activation and loss of cell viability. In addition, there was a significant induction of oxidative mitochondrial DNA damage and elevated cardiolipin peroxidation in insulin-producing RINm5F cells and rat islet cells. Overexpression of the H(2)O(2) detoxifying enzyme catalase effectively reduced the observed cytokine-induced oxidative damage of mitochondrial structures. Taken together, the results strongly indicate that mitochondrial caspase-9 is not a downstream substrate of ER-specific caspase-12 and that pro-inflammatory cytokines cause apoptotic beta cell death through activation of caspase-9 primarily by hydroxyl radical-mediated mitochondrial damage.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Ilir
authors.initials: I
authors.lastname: Mehmeti
authors.forename: Ewa
authors.initials: E
authors.lastname: Gurgul-Convey
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
authors.forename: Stephan
authors.initials: S
authors.lastname: Lortz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism / Q000502:physiology; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018836:Inflammation Mediators / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D002374:Catalase; C506435:Casp9 protein, rat; D053454:Caspase 12; D053453:Caspase 9