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© The Rockefeller University Press,
0021-9525/2002/6/1151 $5.00
The Journal of Cell Biology, Volume 157, Number 7, June 24, 2002 1151-1160
Article |
Transmission of cell stress from endoplasmic reticulum to mitochondria
: enhanced expression of Lon protease
2 Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan
3 Discovery Research Lab, TANABE SEIYAKU Co., Ltd., Osaka City, Osaka 532-0031, Japan
4 Skirball Institute, New York University School of Medicine, New York, NY 10016
5 Departments of Surgery, Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032
6 CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan
Address correspondence to Dr. Osamu Hori, Department of Neuroanatomy (Anatomy III), Kanazawa University, School of Medicine, 13-1 Takara-Machi, Kanazawa City, Ishikawa, 920-8640, Japan. Tel.: 81-76-265-2162. Fax: 81-76-234-4222. E-mail: osamuh{at}nanat.m.kanazawa-u.ac.jp
The rat homologue of a mitochondrial ATP-dependent protease Lon was cloned from cultured astrocytes exposed to hypoxia. Expression of Lon was enhanced in vitro by hypoxia or ER stress, and in vivo by brain ischemia. These observations suggested that changes in nuclear gene expression (Lon) triggered by ER stress had the potential to impact important mitochondrial processes such as assembly and/or degradation of cytochrome c oxidase (COX). In fact, steady-state levels of nuclear-encoded COX IV and V were reduced, and mitochondrial-encoded subunit II was rapidly degraded under ER stress. Treatment of cells with cycloheximide caused a similar imbalance in the accumulation of COX subunits, and enhanced mRNA for Lon and Yme1, the latter another mitochondrial ATP-dependent protease. Furthermore, induction of Lon or GRP75/mtHSP70 by ER stress was inhibited in PERK (-/-) cells. Transfection studies revealed that overexpression of wild-type or proteolytically inactive Lon promoted assembly of COX II into a COX I–containing complex, and partially prevented mitochondrial dysfunction caused by brefeldin A or hypoxia. These observations demonstrated that suppression of protein synthesis due to ER stress has a complex effect on the synthesis of mitochondrial-associated proteins, both COX subunits and ATP-dependent proteases and/or chaperones contributing to assembly of the COX complex.
Key Words: hypoxia; ER stress; protein synthesis; ATP-dependent protease; molecular chaperone
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J. Cell Biol. 2002 157: 1100-1101.
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