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Title: Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila

Abstract

Despite the essential role of mitochondria in a variety of mammalian cell death processes, the involvement of mitochondrial pathway in Drosophila cell death has remained unclear. To address this, we cloned and characterized DmHtrA2, a Drosophila homolog of a mitochondrial serine protease HtrA2/Omi. We show that DmHtrA2 normally resides in mitochondria and is up-regulated by UV-irradiation. Upon receipt of apoptotic stimuli, DmHtrA2 is translocated to extramitochondrial compartment; however, unlike its mammalian counterpart, the extramitochondrial DmHtrA2 does not diffuse throughout the cytosol but stays near the mitochondria. RNAi-mediated knock-down of DmHtrA2 in larvae or adult flies results in a resistance to stress stimuli. DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1), a cellular caspase inhibitor, and induces cell death both in vitro and in vivo as potent as other fly cell death proteins. Our observations suggest that DmHtrA2 promotes cell death through a cleavage of DIAP1 in the vicinity of mitochondria, which may represent a prototype of mitochondrial cell death pathway in evolution.

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [7]
  1. Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536 (United States)
  2. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502 (Japan)
  3. Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
  4. Laboratories for Integrated Biology, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871 (Japan)
  5. (Japan)
  6. Department of Neurology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyoku, Kyoto 606-8507 (Japan). E-mail: ryosuket@kuhp.kyoto-u.ac.jp
  7. Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan). E-mail: miura@mol.f.u-tokyo.ac.jp
Publication Date:
OSTI Identifier:
20991347
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 356; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2007.03.079; PII: S0006-291X(07)00573-6; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; APOPTOSIS; DROSOPHILA; IN VITRO; IN VIVO; IRRADIATION; MITOCHONDRIA; PROTEINS; SERINE; STIMULI

Citation Formats

Igaki, Tatsushi, Suzuki, Yasuyuki, Tokushige, Naoko, Aonuma, Hiroka, Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Takahashi, Ryosuke, and Miura, Masayuki. Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2007.03.079.
Igaki, Tatsushi, Suzuki, Yasuyuki, Tokushige, Naoko, Aonuma, Hiroka, Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Takahashi, Ryosuke, & Miura, Masayuki. Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila. United States. doi:10.1016/j.bbrc.2007.03.079.
Igaki, Tatsushi, Suzuki, Yasuyuki, Tokushige, Naoko, Aonuma, Hiroka, Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Takahashi, Ryosuke, and Miura, Masayuki. Fri . "Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila". United States. doi:10.1016/j.bbrc.2007.03.079.
@article{osti_20991347,
title = {Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila},
author = {Igaki, Tatsushi and Suzuki, Yasuyuki and Tokushige, Naoko and Aonuma, Hiroka and Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 and Takahashi, Ryosuke and Miura, Masayuki},
abstractNote = {Despite the essential role of mitochondria in a variety of mammalian cell death processes, the involvement of mitochondrial pathway in Drosophila cell death has remained unclear. To address this, we cloned and characterized DmHtrA2, a Drosophila homolog of a mitochondrial serine protease HtrA2/Omi. We show that DmHtrA2 normally resides in mitochondria and is up-regulated by UV-irradiation. Upon receipt of apoptotic stimuli, DmHtrA2 is translocated to extramitochondrial compartment; however, unlike its mammalian counterpart, the extramitochondrial DmHtrA2 does not diffuse throughout the cytosol but stays near the mitochondria. RNAi-mediated knock-down of DmHtrA2 in larvae or adult flies results in a resistance to stress stimuli. DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1), a cellular caspase inhibitor, and induces cell death both in vitro and in vivo as potent as other fly cell death proteins. Our observations suggest that DmHtrA2 promotes cell death through a cleavage of DIAP1 in the vicinity of mitochondria, which may represent a prototype of mitochondrial cell death pathway in evolution.},
doi = {10.1016/j.bbrc.2007.03.079},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 356,
place = {United States},
year = {Fri May 18 00:00:00 EDT 2007},
month = {Fri May 18 00:00:00 EDT 2007}
}