title: Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease.
abstract: 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.
authors.affiliation: Department of Neuroanatomy, Kanazawa University, School of Medicine, Kanazawa City, Ishikawa 920-8640, Japan. osamuh@nanat.m.kanazawa-u.ac.jp
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
authors.forename: Fusae
authors.initials: F
authors.lastname: Ichinoda
authors.forename: Takashi
authors.initials: T
authors.lastname: Tamatani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Naoya
authors.initials: N
authors.lastname: Sato
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ozawa
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.forename: Mayuki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Masaya
authors.initials: M
authors.lastname: Tohyama
authors.forename: David
authors.initials: D
authors.lastname: M Stern
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D049069:ATP-Dependent Proteases; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D003513:Cycloheximide / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats; D029701:Saccharomyces cerevisiae Proteins; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D003513:Cycloheximide; D003576:Electron Transport Complex IV; D049069:ATP-Dependent Proteases; D012697:Serine Endopeptidases; C082702:YME1 protein, S cerevisiae; D000251:Adenosine Triphosphatases