Transmission of cell stress from endoplasmic reticulum to mitochondria

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.

Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells

“…2b). Hypoxia and ER stress increase expression of lon protease [10]. Since cholesterol and palmitate triggered ER stress, the influences of this treatment on expression of lon protease were investigated.…”

“…Additionally, lon protease exhibits chaperon-like functions that are independent of its proteolytic activity. Lon protease is also necessary for the assembly of mitochondrial electron transport chain complexes, especially COX II [10,11]. Indeed, in the absence of Pim1, yeast becomes respiratorydeficient because it is unable to maintain mDNA, leading to accumulatin of electron-dense inclusion bodies in the mitochondrial matrix [12].…”

Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer

“…PRSS15 is a multifunctional protein widely preserved throughout species from yeast to mammals (Lu et al, 2003). Its expression, in a rat model and in the human HeLa cell line, has been found to be induced by hypoxia (Hori et al, 2002). HeLa cells transfected with PRSS15 were relatively more resistant to the decrease in mitochondrial membrane potential induced by hypoxia than the mocktransfected cells (Hori et al, 2002).…”

“…Its expression, in a rat model and in the human HeLa cell line, has been found to be induced by hypoxia (Hori et al, 2002). HeLa cells transfected with PRSS15 were relatively more resistant to the decrease in mitochondrial membrane potential induced by hypoxia than the mocktransfected cells (Hori et al, 2002). Human PRSS15 binds to TG-rich elements, where it is presented in the context of a single DNA strand.…”

Mitochondrial Lon protease regulates mitochondrial DNA copy number and transcription by selective degradation of mitochondrial transcription factor A (TFAM)

“…In bacteria, in addition to proteolysis of damaged proteins, Lon also plays a key role in turnover of specific unstable proteins involved in a variety of biological processes (3,4). Similarly, the steroidogenic acute regulatory protein StAR, several subunits of cytochrome c oxidase, and oxidized mitochondrial aconitase are known to be Lon substrates in animal mitochondria (10)(11)(12)(13)(14).…”