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: Osamu Hori, Fusae Ichinoda, Takashi Tamatani, Atsushi Yamaguchi, Naoya Sato, Kentaro Ozawa, Yasuko Kitao, Mayuki Miyazaki, Heather P Harding, David Ron, Masaya Tohyama, David M Stern, Satoshi Ogawa
• Journal: The Journal of cell biology (J Cell Biol) Vol. 157 Issue 7 Pg. 1151-60 (Jun 24 2002) ISSN: 0021-9525 [Print] United States
• PMID: 12082077 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• HSP70 Heat-Shock Proteins
• Heat-Shock Proteins
• Saccharomyces cerevisiae Proteins
• Cycloheximide
• Electron Transport Complex IV
• ATP-Dependent Proteases
• Serine Endopeptidases
• YME1 protein, S cerevisiae
• Adenosine Triphosphatases

Topics

• ATP-Dependent Proteases
• Adenosine Triphosphatases (metabolism)
• Animals
• Brain Ischemia (metabolism)
• Cell Hypoxia
• Cell Nucleus (enzymology)
• Cells, Cultured
• Cerebral Cortex (cytology, embryology)
• Cycloheximide (pharmacology)
• Electron Transport Complex IV (genetics, metabolism)
• Endoplasmic Reticulum (metabolism)
• Gene Expression Regulation, Enzymologic
• HSP70 Heat-Shock Proteins (metabolism)
• Heat-Shock Proteins (metabolism)
• Humans
• Mitochondria (metabolism)
• Oxidative Stress (physiology)
• Promoter Regions, Genetic
• Rats
• Saccharomyces cerevisiae Proteins
• Serine Endopeptidases (metabolism)