Translocation of the serine protease Omi/HtrA2 from mitochondria into the cytosol upon seizure-induced hippocampal injury in the neonatal rat brain.
Omi/HtrA2 is a pro-apoptotic mitochondrial serine protease involved in caspase-dependent as well as caspase-independent cell death upon various brain injuries. However, the role of Omi/HtrA2 in neuronal death induced by status epilepticus (SE) in the immature brain has not been reported. In this study, we analyzed the contribution of serine protease Omi/HtrA2, its substrate X-linked inhibitor of apoptosis protein (XIAP) and the caspase-3 activation to damage of hippocamplal CA1 cells following lithium-pilocarpine SE in P14 rat pups. Status epilepticus in the immature brain significantly induced translocation of Omi/HtrA2 from mitochondria into the cytosol, increased cytosolic accumulation of Omi/HtrA2, induced appearance of XIAP-breakdown products and enhanced caspase-3 activity in the selectively vulnerable hippocampal CA1-subfield. Taken together, these results demonstrate for the first time that SE in the immature brain results in Omi/HtrA2 accumulation in the cytosol, where it probably promotes neuronal death by neutralizing and cleaving XIAP, one of the most potent endogenous inhibitors of apoptosis.
Dr Senckenbergische Anatomie, Anatomie III, Universitätsklinikum, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany. Rami@em.uni-frankfurt.de
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D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology*; D007120:Immunochemistry; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000378:metabolism* / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; D053148:Caspase 3