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The Roles of Mitochondria-Associated Membranes in Mitochondrial Quality Control Under Endoplasmic Reticulum Stress

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The Roles of Mitochondria-Associated Membranes in Mitochondrial Quality Control Under Endoplasmic Reticulum Stress Life Sciences 231 (2019) 116587 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Review article The roles of mitochondria-associated membranes in mitochondrial quality control under endoplasmic reticulum stress T ⁎ ⁎⁎ Beiwu Lana, Yichun Hea, Hongyu Sunb, Xinzi Zhengb, Yufei Gaoa, ,NaLib, a Department of Neurosurgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China b Department of Pathophysiology, Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China ARTICLE INFO ABSTRACT Keywords: The endoplasmic reticulum (ER) and mitochondria are two important organelles in cells. Mitochondria-asso- Endoplasmic reticulum stress ciated membranes (MAMs) are lipid raft-like domains formed in the ER membranes that are in close apposition Mitochondrial quality control to mitochondria. They play an important role in signal transmission between these two essential organelles. Mitochondria associated membranes When cells are exposed to internal or external stressful stimuli, the ER will activate an adaptive response called Ca2+ the ER stress response, which has a significant effect on mitochondrial function. Mitochondrial quality control is an important mechanism to ensure the functional integrity of mitochondria and the effect of ER stress on mi- tochondrial quality control through MAMs is of great significance. Therefore, in this review, we introduce ER stress and mitochondrial quality control, and discuss how ER stress signals are transmitted to mitochondria through MAMs. We then review the important roles of MAMs in mitochondrial quality control under ER stress. 1. Introduction Accumulating evidence indicates that ER and mitochondrial functions are highly connected physiologically and pathologically. Under stress The endoplasmic reticulum (ER) has a network structure consisting conditions, cells can coordinate ER and mitochondrial functions to re- of rough ER (rER) and smooth ER (sER) and plays important roles in the store cellular homeostasis. Many studies have shown that ER stress has synthesis of proteins and lipids and the storage of Ca2+. Under stress an effect on mitochondrial function, but the detailed mechanism un- conditions, such as starvation or hypoxia, ER homeostasis can be in- derlying this effect has not been established. It has long been known terrupted, which is termed ER stress. When ER stress occurs, ER protein that ER membranes can be in close enough proximity to mitochondria folding and Ca2+ storage abilities are perturbed, leading to unfolded or to form lipid raft-like domains called mitochondria-associated mem- misfolded proteins accumulating in the ER and Ca2+ release from the branes (MAMs). MAMs contain many proteins that physically connect ER, resulting in activation of the ER unfolded protein response (UPRer) the ER and mitochondria and that play important roles in lipid synth- and Ca2+ signal transmission. This can initiate pro-survival or pro- esis and Ca2+ transfer from the ER to mitochondria [8]. There is no death responses, which determine cell fate [1]. Mitochondria are doubt that MAMs are especially important for the transfer of stress composed of inner and outer mitochondrial membranes, the inner mi- signals from the ER to mitochondria and may play an important role in tochondrial membrane space (IMS) and the mitochondrial matrix. Mi- regulating MQC under ER stress (Figs. 1 and 2). tochondria are the location for the intracellular tricarboxylic acid cycle and oxidative phosphorylation, and are the ‘power stations’ of cells. In 2. Two major features of ER stress addition to providing energy, mitochondria are also involved in cell differentiation, cell signaling, and apoptosis [2–4]. Mitochondria have a The ER is mainly responsible for proteins synthesis and folding, lipid self-functioning security mechanism, namely mitochondrial quality synthesis and Ca2+ storage in cells. ER requires a strict steady en- control (MQC). Mitochondria have three levels of quality control. When vironment to function properly. Stimuli, like starvation, hypoxia, can cells are under mild stress, mitochondria can maintain mitochondrial break down the homeostasis of intracellular environment, leading to protein homeostasis and structural integrity to ensure correct function dis-function of the ER, resulting in ER stress [1]. ER stress is an adaptive at molecular and organellar levels. Cells can also initiate mitochondrial response, which has two major features including UPRer and Ca2+ apoptosis to ensure MQC when the stress is too severe [5–7]. homeostasis perturbation. ⁎ Correspondence to: Y. Gao, Department of Neurosurgery, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Changchun 130021, China. ⁎⁎ Correspondence to: N. Li, Key Laboratory of Pathobiology, Jilin University, 126 Xinmin Street, Changchun 130021, Jilin, China. E-mail addresses: [email protected] (Y. Gao), [email protected] (N. Li). https://doi.org/10.1016/j.lfs.2019.116587 Received 4 March 2019; Received in revised form 28 May 2019; Accepted 17 June 2019 Available online 18 June 2019 0024-3205/ © 2019 Elsevier Inc. All rights reserved. B. Lan, et al. Life Sciences 231 (2019) 116587 Fig. 1. Mitochondria-associated membranes (MAMs) and ER stress. MAM-connected proteins include B cell receptor associated protein 31 (Bap31), mitochondrial fission 1 (fis1), tyrosine phosphatase-interacting protein 51 (PTPIP51), vesicle-associated protein (VAPB), PERK, and mitochondrial fusion protein 2 (MFN2). In addition, inositol 1, 4, 5-trisphosphate receptor (IP3R) is linked to voltage- dependent anion channel 1 (VDAC1) through glucose-regulated protein 75 (Grp75), which constitute the Ca2+ channels between the ER and mitochondria. MAMs also contain many chaperones, such as calnexin (CNX), calreticulin (CRT) and sigma 1 receptor (S1R), which play an important role in Ca2+ buffering. MAMs are also important sites for lipid synthesis and shuttling. Phosphatidylserine (PS) is synthesized in the ER and enters the IMS though MAMs to generate phosphatidyletha- nolamine (PE), which can go back to the ER where it will be converted to phosphatidylcholine (PC). Cholesterol acyltransferase (ACAT) is enriched in MAMs and can catalyze the generation of cholesteryl esters. The Miro GTPase 1/2 (miro1/2) is present in the OMM and can regulate mitochondrial movement. Two major features of ER stress include the endoplasmic reticulum unfolded protein response and unbalanced Ca2+ homeostasis. PERK can phosphorylate EIF2α to induce the activating transcription factor, ATF4. It can also phosphorylate nuclear transcription factor 2 (NRF2), activating its transcriptional function. Phosphorylation of IRE1α activates its RNase activity, which can cleave the X-box binding protein 1 (XBP1) mRNA into a tight form that can encode stable sXBP1. Activated ATF6 can dissociate from the ER and translocate to the Golgi where it can be cleaved by a protease into its active form. These transcription factors can translocate to the nucleus to up-regulate expression of genes that determine cell fate. The maintenance of Ca2+ homeostasis in the ER mainly depends on the endoplasmic reticulum Ca2+ ATPase (SERCA) and Ca2+ release channels [Ryanodine receptor (RyR) and inositol 1,4,5-triphate receptor (IP3R)]. When ER stress occurs, SERCA activity is inhibited and RyR and IP3R are activated, leading to Ca2+ homeostasis imbalance. 2.1. UPRer reduces ER protein folding load and selectively up-regulates activating transcription factor 4 (ATF4) expression. ATF4 is a double-edged sword, The UPRer is an adaptive response that is activated under stress which not only promotes the expression of anti-apoptotic proteins, but when nascent peptide cannot be folded or is misfolded, leading accu- also increases the expression of pro-apoptotic proteins by up-regulating mulation of non-functional proteins in the ER [9]. PERK, IRE1α and CHOP [14]. Phosphorylation of IRE1α activates its RNase activity, ATF6 are three transmembrane proteins in the ER. Under normal con- which can cleave the X-box binding protein 1 (XBP1) mRNA into a tight ditions, they bind to the chaperone, Bip, and remain in an inactive state. form that can encode stable sXBP1 [15]. sXBP1 is a transcription factor When ER stress occurs, Bip can sense the unfolded/misfolded proteins that can up-regulate genes related to ER chaperones and ER-associated and dissociates from these three transmembrane proteins resulting to degradation (ERAD) [16]. In addition, the RNase activity of IRE1 can their activation [10]. Activated PERK can phosphorylate nuclear tran- degrade many RNA substrates reducing the protein folding load in the scription factor 2 (NRF2) and the eukaryotic initiation factor 2 (EIF2α) ER. This process is also known as regulatory IRE1-dependent de- [11,12]. Phosphorylated NRF2 can translocate to the nucleus to up- gradation (RIDD) [17]. After activation, ATF6 can dissociate from the regulate redox-related proteins to ensure redox homeostasis [13]. ER and translocate to the Golgi where it can be cleaved by a protease Phosphorylated EIF2α can inhibit global mRNA translation, which into an activated form. This can then transfer to the nucleus and up- 2 B. Lan, et al. Life Sciences 231 (2019) 116587 Fig. 2. The roles of mitochondria-associated membranes (MAMs) in mitochondrial quality control (MQC) under ER stress. At molecular level MQC, the PERK/EIFα/ATF4 axis can decrease mitochondrial protein import and
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