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Translocation of the Serine Protease Omi/HtrA2 from Mitochondria into the Cytosol Upon Seizure-Induced Hippocampal Injury in the Neonatal Rat Brain

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Abstract

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.

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Acknowledgments

We are grateful to Angelika Langhagen for technical assistance. This work was funded in part by research grant from the Adolf-Messer-Stiftung (Grant to Dr. A. Rami).

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Authors and Affiliations

  1. Dr. Senckenbergische Anatomie, Anatomie III, Universitätsklinikum, Theodor-Stern-Kai 7, 60590, Frankfurt/Main, Germany

    A. Rami

  2. Institut für Zelluläre und Molekulare Anatomie (Anatomie III), Klinikum der Johann Wolfgang von Goethe-Universität, Theodor-Stern-Kai 7, 60590, Franfurt/Main, Germany

    A. Rami & M. Kim

  3. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA

    J. Niquet

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  1. A. Rami
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  2. M. Kim
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Correspondence to A. Rami.

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This article is for the Special Issue in honor of Dr. Abel Lajtha.

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Rami, A., Kim, M. & Niquet, J. Translocation of the Serine Protease Omi/HtrA2 from Mitochondria into the Cytosol Upon Seizure-Induced Hippocampal Injury in the Neonatal Rat Brain. Neurochem Res 35, 2199–2207 (2010). https://doi.org/10.1007/s11064-010-0322-0

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