title: Loss of caspase-2-dependent apoptosis induces autophagy after mitochondrial oxidative stress in primary cultures of young adult cortical neurons.
abstract: Mitochondrial dysfunctions have been associated with neuronal apoptosis and are characteristic of neurodegenerative conditions. Caspases play a central role in apoptosis; however, their involvement in mitochondrial dysfunction-induced neuronal apoptosis remains elusive. In the present report using rotenone, a complex I inhibitor that causes mitochondrial dysfunction, we determined the initiator caspase and its role in cell death in primary cultures of cortical neurons from young adult mice (1-2 months old). By pretreating the cells with a cell-permeable, biotinylated pan-caspase inhibitor that irreversibly binds to and traps the active caspase, we identified caspase-2 as an initiator caspase activated in rotenone-treated primary neurons. Loss of caspase-2 inhibited rotenone-induced apoptosis; however, these neurons underwent a delayed cell death by necrosis. We further found that caspase-2 acts upstream of mitochondria to mediate rotenone-induced apoptosis in neurons. The loss of caspase-2 significantly inhibited rotenone-induced activation of Bid and Bax and the release of cytochrome c and apoptosis inducing factor from mitochondria. Rotenone-induced downstream activation of caspase-3 and caspase-9 were also inhibited in the neurons lacking caspase-2. Autophagy was enhanced in caspase-2 knock-out neurons after rotenone treatment, and this response was important in prolonging neuronal survival. In summary, the present study identifies a novel function of caspase-2 in mitochondrial oxidative stress-induced apoptosis in neurons cultured from young adult mice.
authors.affiliation: From the Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Tiwari
authors.affiliation: From the Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: Marisa
authors.initials: M
authors.lastname: Lopez-Cruzan
authors.affiliation: From the Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229.
authors.forename: William W
authors.initials: WW
authors.lastname: Morgan
authors.affiliation: From the Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229. Electronic address: hermanb@uthscsa.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Herman
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D009474:Neurons / Q000201:enzymology*; D018384:Oxidative Stress; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D014475:Uncoupling Agents; D051028:bcl-2-Associated X Protein; D012402:Rotenone; D045304:Cytochromes c; C090208:Casp2 protein, mouse; D053143:Caspase 2