Abstract 抽象的
Dynamic interactions between organelles are responsible for a variety of intercellular functions, and the endoplasmic reticulum (ER)–mitochondrial axis is recognized as a representative interorganelle system. Several studies have confirmed that most proteins in the physically tethered sites between the ER and mitochondria, called mitochondria-associated ER membranes (MAMs), are vital for intracellular physiology. MAM proteins are involved in the regulation of calcium homeostasis, lipid metabolism, and mitochondrial dynamics and are associated with processes related to intracellular stress conditions, such as oxidative stress and unfolded protein responses. Accumulating evidence has shown that, owing to their extensive involvement in cellular homeostasis, alterations in the ER–mitochondrial axis are one of the etiological factors of tumors. An in-depth understanding of MAM proteins and their impact on cell physiology, particularly in cancers, may help elucidate their potential as diagnostic and therapeutic targets for cancers. For example, the modulation of MAM proteins is utilized not only to target diverse intracellular signaling pathways within cancer cells but also to increase the sensitivity of cancer cells to anticancer reagents and regulate immune cell activities. Therefore, the current review summarizes and discusses recent advances in research on the functional roles of MAM proteins and their characteristics in cancers from a diagnostic perspective. Additionally, this review provides insights into diverse therapeutic strategies that target MAM proteins in various cancer types.
细胞器之间的动态相互作用负责多种细胞间功能,内质网(ER)-线粒体轴被认为是代表性的细胞器间系统。几项研究已证实,位于 ER 和线粒体之间的物理束缚位点(称为线粒体相关 ER 膜 (MAM))中的大多数蛋白质对于细胞内生理学至关重要。 MAM 蛋白参与钙稳态、脂质代谢和线粒体动力学的调节,并与细胞内应激条件相关的过程相关,例如氧化应激和未折叠蛋白反应。越来越多的证据表明,由于内质网-线粒体轴广泛参与细胞稳态,其改变是肿瘤的病因之一。深入了解 MAM 蛋白及其对细胞生理学的影响,尤其是对癌症的影响,可能有助于阐明它们作为癌症诊断和治疗靶点的潜力。例如,MAM蛋白的调节不仅用于靶向癌细胞内的多种细胞内信号传导途径,还用于增加癌细胞对抗癌试剂的敏感性并调节免疫细胞活性。因此,本文从诊断的角度总结和讨论了MAM蛋白的功能作用及其在癌症中的特征的研究最新进展。此外,这篇综述还提供了针对各种癌症类型中针对 MAM 蛋白的多种治疗策略的见解。
Subject terms: Mechanisms of disease, Stress signalling
主题术语:疾病机制、应激信号
MAM proteins: the hidden players in cancer diagnostics and therapy
MAM 蛋白:癌症诊断和治疗中的隐藏参与者
Understanding the cooperation between organelles, especially the endoplasmic reticulum and mitochondria (the energy factories of cells), is vital to uncover how cellular functions are controlled. However, the exact function of the membranes linking these organelles, termed mitochondria-associated ER membranes (MAMs), in diseases like cancer is still uncertain. In this research, scientists found MAMs to play a vital role in cancer cell function and metabolism by regulating calcium signaling, lipid metabolism, autophagy, and mitochondrial fission. They discovered that changes in MAM proteins can result in inhibition of apoptosis and increased resistance to anticancer drugs. Therefore, therapies targeting MAMs may provide a new method for cancer treatment. The researchers also propose that MAM proteins could be used as diagnostic markers for specific cancers.
了解细胞器之间的合作,特别是内质网和线粒体(细胞的能量工厂)之间的合作,对于揭示细胞功能是如何控制的至关重要。然而,连接这些细胞器的膜(称为线粒体相关内质网膜(MAM))在癌症等疾病中的确切功能仍不确定。在这项研究中,科学家发现 MAM 通过调节钙信号传导、脂质代谢、自噬和线粒体裂变,在癌细胞功能和代谢中发挥着至关重要的作用。他们发现 MAM 蛋白的变化可以抑制细胞凋亡并增加抗癌药物的耐药性。因此,针对MAM的治疗可能为癌症治疗提供新方法。研究人员还提出,MAM 蛋白可以用作特定癌症的诊断标记物。
This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
该摘要最初是使用人工智能起草的,然后由作者进行修改和事实核查。
Introduction 介绍
An understanding of the cooperation between organelles is crucial for revealing the mechanisms that modulate cellular functions and homeostasis. Among interorganellar networks, the connection between the endoplasmic reticulum (ER) and mitochondria has been extensively studied owing to its diverse functions and impact on the pathogenesis of multiple diseases. The concept of a functional unit comprising the ER and mitochondria was first proposed in 19501. The adjacent membrane sites that physically tether the ER and mitochondria are called mitochondria-associated ER membranes (MAMs); technological advances in microscopy have enabled the elucidation of the physiological features of the tethering structures of the MAMs. The ER and mitochondria are separated by a 6–15 nm gap, and the average surface area percentage of mitochondria covered by MAMs was calculated to be 3–5% in mammalian cells2.
了解细胞器之间的合作对于揭示调节细胞功能和稳态的机制至关重要。在细胞器间网络中,内质网(ER)和线粒体之间的联系因其多样化的功能和对多种疾病发病机制的影响而被广泛研究。由 ER 和线粒体组成的功能单位的概念于 1950 年首次提出1 。物理连接 ER 和线粒体的相邻膜位点称为线粒体相关 ER 膜 (MAM);显微镜技术的进步使得能够阐明 MAM 系链结构的生理特征。 ER 和线粒体之间有 6–15 nm 的间隙,在哺乳动物细胞中,MAM 覆盖的线粒体平均表面积百分比经计算为 3–5% 2 。
MAMs represent an etiological and therapeutic target in cardiovascular diseases3, neurodegenerative diseases4, metabolic disorders5,6, and cancers. In this review, we discuss the associations between alterations in MAM proteins and cancers and present recent advances in research on these associations. Additionally, we discuss the contribution of MAM proteins to tumorigenesis and cancer progression as well as their possible applications as diagnostic and therapeutic targets.
MAM 代表心血管疾病3 、神经退行性疾病4 、代谢紊乱5 、 6和癌症的病因学和治疗靶点。在这篇综述中,我们讨论了 MAM 蛋白的改变与癌症之间的关联,并介绍了这些关联研究的最新进展。此外,我们还讨论了 MAM 蛋白对肿瘤发生和癌症进展的贡献以及它们作为诊断和治疗靶点的可能应用。
Structure and functional role of ER–mitochondria contact sites
ER-线粒体接触位点的结构和功能作用
Calcium regulation 钙调节
Maintenance of Ca2+ homeostasis is one of the most important functions of MAMs, as the ER functions as the main regulator and storage organelle of calcium ions within living cells7. The resting levels of Ca2+ in mitochondria are similar to those in the cytosol; however, they can increase to 100 times the cytosolic levels under specific stimulation conditions8. A contributing factor to this drastic increase has been identified and subsequently confirmed by the Ca2+ microdomain hypothesis, which states that the outer membrane of mitochondria contains hotspots for Ca2+ shuttling from the ER9–11. As the affinity of the mitochondrial calcium uniporter (MCU) located in the inner mitochondrial membrane is dependent on the local Ca2+ concentration, these microdomains facilitate Ca2+ influx through the MCU12,13.
维持 Ca 2+稳态是 MAM 最重要的功能之一,因为 ER 是活细胞内钙离子的主要调节器和储存细胞器7 。线粒体中Ca 2+的静息水平与细胞质中的相似;然而,在特定的刺激条件下,它们可以增加到细胞质水平的 100 倍8 。 Ca 2+微域假说已确定并随后证实了导致这种急剧增加的一个因素,该假说指出线粒体外膜包含 Ca 2+从 ER 9 – 11穿梭的热点。由于位于线粒体内膜中的线粒体钙单向转运蛋白(MCU)的亲和力取决于局部Ca 2+浓度,因此这些微结构域促进Ca 2+通过MCU流入12、13 。
The translocation of Ca2+ in MAMs is mediated by several proteins. The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a representative Ca2+ channel located in the ER14 (Fig. 1). The opening of this receptor and subsequent Ca2+ transport occur when the binding site of each tetrameric subunit of IP3R is concatenated with IP315. The IP3 binding affinity and Ca2+ influx activity of IP3R vary depending on its subtype16, phosphorylation17, and interactions with other regulatory proteins. Additionally, recent research has shown that the localization of mobile IP3R on MAMs is important for Ca2+ signaling between the ER and mitochondria18.
MAM 中 Ca 2+的易位由多种蛋白质介导。肌醇1,4,5-三磷酸(IP3)受体(IP3R)是位于ER 14中的代表性Ca 2+通道(图1 )。当IP3R的每个四聚亚基的结合位点与IP3 15连接时,该受体的打开和随后的Ca 2+转运发生。 IP3R 的 IP3 结合亲和力和 Ca 2+流入活性根据其亚型16 、磷酸化17以及与其他调节蛋白的相互作用而变化。此外,最近的研究表明,MAM 上移动 IP3R 的定位对于 ER 和线粒体之间的 Ca 2+信号传导非常重要18 。
The canonical microdomain of the Ca2+ regulator in MAMs consists of IP3R located in the ER, voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane (OMM), and glucose-regulated protein 75 (GRP75), which acts as a physical link between IP3R and VDAC1 and directly affects mitochondrial Ca2+ accumulation19. The formation of these complexes brings the ER and mitochondria into close proximity, resulting in the formation of microdomains with high Ca2+ levels20,21. Recent evidence has indicated the importance of another protein component within this microdomain. DJ-1 was recognized as the fourth component of the MAM complex through the observation that DJ-1 ablation induced IP3R3 aggregation, which prevented the tethering of the IP3R-GRP75-VDAC microdomain22.
MAM 中 Ca 2+调节器的典型微结构域由位于 ER 中的 IP3R、线粒体外膜 (OMM) 中的电压依赖性阴离子通道 1 (VDAC1) 和葡萄糖调节蛋白 75 (GRP75) 组成,该蛋白充当IP3R 和 VDAC1 之间的物理联系,直接影响线粒体 Ca 2+积累19 。这些复合物的形成使 ER 和线粒体非常接近,从而形成具有高 Ca 2+水平的微区20 , 21 。最近的证据表明该微域内另一种蛋白质成分的重要性。通过观察 DJ-1 消融诱导 IP3R3 聚集,从而阻止 IP3R-GRP75-VDAC 微域的束缚,DJ-1 被认为是 MAM 复合物的第四个组成部分22 。
In addition to the IP3R-GRP75-VDAC1 complex, the interaction of ER-integrated protein vesicle-associated membrane protein B (VAPB) with the OMM protein called protein tyrosine phosphatase-interacting protein-51 (PTPIP51) is also involved in Ca2+ regulation. Depletion of either VAPB or PTPIP51 leads to the disruption of MAMs and perturbation of Ca2+ transport23.
除了 IP3R-GRP75-VDAC1 复合物之外,ER 整合蛋白囊泡相关膜蛋白 B (VAPB) 与称为蛋白酪氨酸磷酸酶相互作用蛋白 51 (PTPIP51) 的 OMM 蛋白的相互作用也参与 Ca 2+规定。 VAPB 或 PTPIP51 的消耗会导致 MAM 的破坏和 Ca 2+运输的扰动23 。
Lipid metabolism 脂质代谢
Because lipid synthesis is compartmentalized, lipids must be transferred between organelle compartments. Lipids shuttle between specific organelles through vesicle trafficking; however, lipid influx into mitochondria through vesicles is not possible even when lipids are needed24. Thus, several MAM proteins regulate the nonvesicular trafficking of lipids from the ER to mitochondria (Fig. 1). Phosphatidylserine synthase 1/2 (PSS1/2) is a representative synthetic enzyme that is enriched in MAMs and mediates phosphatidylserine (PS) synthesis25. Specifically, PSS1 and PSS2 convert phosphatidylcholine (PC) and phosphatidylethanolamine (PE), respectively, into PS. PE import relies on the conversion of transported PS in MAMs to PE by PS decarboxylase (PSD) in mitochondria rather than direct import26. Disruption of this process and the mitochondrial PE level impairs mitochondrial dynamics and bioenergetics27,28. Mitochondrial PE can be traced back to MAMs and is converted into PC by PE-N-methyltransferase29. This transfer system is the rate-limiting step in lipid biogenesis and further contributes to the maintenance of phospholipid homeostasis.
由于脂质合成是区室化的,因此脂质必须在细胞器区室之间转移。脂质通过囊泡运输在特定细胞器之间穿梭;然而,即使需要脂质,脂质也不可能通过囊泡流入线粒体24 。因此,几种MAM蛋白调节脂质从ER到线粒体的非囊泡运输(图1 )。磷脂酰丝氨酸合酶 1/2 (PSS1/2) 是一种代表性的合成酶,富含 MAM,介导磷脂酰丝氨酸 (PS) 合成25 。具体来说,PSS1和PSS2分别将磷脂酰胆碱(PC)和磷脂酰乙醇胺(PE)转化为PS。 PE 输入依赖于线粒体中 PS 脱羧酶 (PSD) 将 MAM 中转运的 PS 转化为 PE,而不是直接输入26 。该过程和线粒体 PE 水平的破坏会损害线粒体动力学和生物能学27 , 28 。线粒体 PE 可以追溯到 MAM,并通过 PE- N-甲基转移酶29转化为 PC。该转移系统是脂质生物发生的限速步骤,并进一步有助于维持磷脂稳态。
The complex consisting of Mdm10 and Mdm34 is located in the OMM, and Mmm1 in the ER and Mdm12 in the cytosol exhibit features of ER–mitochondria tethering proteins and phospholipid exchangers30. Mdm34, Mmm1, and Mdm12 physically interact with phospholipids via their synaptotagmin-like mitochondrial lipid-binding domains31–33. The direct binding of Mmm1 and Mdm12 forms a hydrophobic cavity that mediates the transport of glycerophospholipids except for PE34. However, as the depletion of this complex only exerts minor effects on the lipidome, more unknown lipid regulatory proteins and mechanisms may exist in MAMs30.
由 Mdm10 和 Mdm34 组成的复合物位于 OMM 中,ER 中的 Mmm1 和胞质溶胶中的 Mdm12 表现出 ER-线粒体束缚蛋白和磷脂交换剂的特征30 。 Mdm34、Mmm1 和 Mdm12 通过其突触结合蛋白样线粒体脂质结合域与磷脂发生物理相互作用31 – 33 。 Mmm1 和 Mdm12 的直接结合形成疏水空腔,介导除 PE 34之外的甘油磷脂的运输。然而,由于该复合物的消耗仅对脂质组产生较小影响,因此 MAM 中可能存在更多未知的脂质调节蛋白和机制30 。
Regulation of mitochondrial dynamics
线粒体动力学的调节
Mitochondrial quality control is a defense mechanism against mitochondrial insult. In the early stages of quality control, translocation and recruitment of dynamin-related protein (DRP1) in mitochondria occurs in MAMs and facilitates mitochondrial fission35. In contrast, mitofusin 1 (MFN1), another MAM protein, forms puncta in the ER and facilitates mitochondrial fusion36. Physical tethering of the ER to mitochondria by MFN1/2 indicates the importance of MAMs as key sites for regulating mitochondrial dynamics37,38 (Fig. 1).
线粒体质量控制是针对线粒体损伤的防御机制。在质量控制的早期阶段,线粒体中动力相关蛋白 (DRP1) 的易位和募集发生在 MAM 中,并促进线粒体裂变35 。相反,另一种 MAM 蛋白线粒体融合蛋白 1 (MFN1) 在 ER 中形成斑点并促进线粒体融合36 。 MFN1/2 将 ER 与线粒体物理束缚,表明 MAM 作为调节线粒体动力学关键位点的重要性37 、 38 (图1 )。
In addition to fission and fusion, self-degradation of mitochondria upon severe injury, a process called mitophagy, is also influenced by MAM proteins. The PTEN-induced putative kinase (PINK)/parkin pathway is the main signaling pathway for mitophagy. PINK is degraded by mitochondria-resident enzymes and further degraded in lysosomes under normal conditions; however, mitochondrial dysfunction leads to the formation of uncleaved PINK and its accumulation in the OMM through an interaction with TOM39. The accumulated PINK proteins recruit parkin, which induces mitophagy through its E3 ligase activity39,40. A recent study reported that PINK1/Parkin mediate MFN2 phosphorylation, resulting in the dissociation of the MFN2 complex via the p97-dependent pathway. This indicates a relationship between a decrease in ER–mitochondrial contact and mitophagy41. Additionally, assembly of the autophagosome marker ATG14 occurs in MAMs under starvation conditions, and disruption of the ER–mitochondria interaction inhibits ATG14 localization and autophagosome formation42.
除了裂变和融合之外,线粒体在严重损伤时的自我降解(称为线粒体自噬)也受到 MAM 蛋白的影响。 PTEN 诱导的推定激酶 (PINK)/parkin 通路是线粒体自噬的主要信号通路。 PINK被线粒体驻留酶降解,并在正常条件下在溶酶体中进一步降解;然而,线粒体功能障碍导致未切割的 PINK 的形成,并通过与 TOM 39 的相互作用在 OMM 中积累。积累的 PINK 蛋白招募 Parkin,通过其 E3 连接酶活性诱导线粒体自噬39 , 40 。最近的一项研究报道,PINK1/Parkin 介导 MFN2 磷酸化,导致 MFN2 复合物通过 p97 依赖性途径解离。这表明内质网-线粒体接触的减少与线粒体自噬之间存在关系41 。此外,在饥饿条件下,MAM 中会发生自噬体标记 ATG14 的组装,并且 ER-线粒体相互作用的破坏会抑制 ATG14 定位和自噬体形成42 。
Interaction between the ER–mitochondrial axis and calcium homeostasis
ER-线粒体轴与钙稳态之间的相互作用
Most ER proteins are involved in regulating Ca2+ homeostasis43. For instance, the sigma-1 receptor (Sig-1R), a MAM protein, is enriched in the ER vesicles involved in this process. In the resting state, Sig-1R binds to another chaperone in the ER, GRP78. However, this complex dissociates under ER stress conditions, including Ca2+ depletion. The dissociated Sig-1R then binds to IP3R, mediating its stabilization and Ca2+ influx44. PDZ domain-containing protein 8 (PDZD8) in the ER is another example of a Ca2+-regulating protein in MAMs. PDZD8 knockdown impairs ER–mitochondria tethering and further inhibits mitochondrial Ca2+ uptake in the MAMs of mammalian neurons45. Other proteins modulate calcium homeostasis in MAMs, as shown in Table 1.
大多数 ER 蛋白参与调节 Ca 2+稳态43 。例如,sigma-1 受体 (Sig-1R)(一种 MAM 蛋白)在参与该过程的 ER 囊泡中富集。在静息状态下,Sig-1R 与 ER 中的另一个伴侣 GRP78 结合。然而,该复合物在内质网应激条件下(包括 Ca 2+耗尽)会解离。然后解离的 Sig-1R 与 IP3R 结合,介导其稳定和 Ca 2+流入44 。 ER 中含有 PDZ 结构域的蛋白 8 (PDZD8) 是 MAM 中 Ca 2+调节蛋白的另一个例子。 PDZD8 敲低会损害 ER-线粒体束缚,并进一步抑制哺乳动物神经元 MAM 中线粒体 Ca 2+ 的摄取45 。其他蛋白质调节 MAM 中的钙稳态,如表1所示。
Table 1. 表 1.
Name 姓名 | Cells 细胞 | Possible mechanisms 可能的机制 |
---|---|---|
Sig-1R (sigma-1 receptor) Sig-1R(sigma-1 受体) |
CHO cells CHO细胞 | Mediates stabilizing IP3R and Ca2+ influx when dissociated from BIP 从 BIP 解离时介导稳定 IP3R 和 Ca 2+流入 |
Mouse, NRVM cells 小鼠,NRVM 细胞 | Maintains the close proximity between IP3R2 and VDAC by interacting with IP3R2 通过与 IP3R2 交互,保持 IP3R2 和 VDAC 之间的紧密接近 |
|
PDZD8 (PDZ domain-containing protein 8) PDZD8(含 PDZ 结构域的蛋白 8) |
Cortical pyramidal neurons, Drosophila 皮质锥体神经元,果蝇 |
Mediates the tethering of EMCSs and mitochondrial uptake of Ca2+ through MCU 通过 MCU 介导 EMCS 的束缚和线粒体对 Ca 2+的摄取 |
ALKBH5 (RNA demethylase alkb homolog 5) ALKBH5(RNA 去甲基化酶 alkb 同源物 5) |
143B, MG53, IMR90, and HEK293T cells 143B、MG53、IMR90 和 HEK293T 细胞 |
Modulates ER lipid raft associated 1 (ERLIN1)-IP3R Ca2+ signaling via hypermethylation of ERLIN1 mRNA 通过ERLIN1 mRNA 的高甲基化调节 ER 脂筏相关 1 (ERLIN1)-IP 3 R Ca 2+信号传导 |
FMRP (fragile X messenger ribonucleoprotein) FMRP(脆性 X 信使核糖核蛋白) |
Drosophila, Mouse, U2OS, HEK293T, HeLa, and normal/patient derived fibroblasts 果蝇、小鼠、U2OS、HEK293T、HeLa 和正常/患者来源的成纤维细胞 |
Regulates Ca2+ homeostasis by interacting with VDAC; loss of FMRP leads to excessive Ca2+ influx into mitochondria 通过与 VDAC 相互作用调节 Ca 2+稳态; FMRP 缺失导致过量 Ca 2+流入线粒体 |
TG2 (transglutaminase type 2) TG2(2 型转谷氨酰胺酶) |
CAD cells CAD 单元 | Increases the number of IP3R-VDAC1 units through crosslinking amyloid beta 通过交联淀粉样蛋白 β 增加 IP3R-VDAC1 单位的数量 |
HEK293 cells HEK293细胞 | Increases the number of EMCSs by interacting with GRP75 and increasing the formation of the IP3R-GRP75-VDAC1 complex 通过与 GRP75 相互作用并增加 IP 3 R-GRP75-VDAC1 复合物的形成来增加 EMCS 的数量 |
|
STING (stimulator of interferon response cGAMP interactor 1) STING(干扰素反应刺激物 cGAMP 相互作用子 1) |
Human renal carcinoma cell lines 人肾癌细胞系 |
Interferes with interactions between VDAC1 and GRP75 by binding to VDAC1 in renal cancer cells 通过与肾癌细胞中的 VDAC1 结合来干扰 VDAC1 和 GRP75 之间的相互作用 |
Pyk2 (proline-rich tyrosine kinase 2) Pyk2(富含脯氨酸的酪氨酸激酶 2) |
Mouse primary neuronal cells 小鼠原代神经元细胞 |
Increases the number of EMCSs by regulating the protein expression levels of IP3R3 and VDAC1 通过调节 IP3R3 和 VDAC1 的蛋白表达水平来增加 EMCS 的数量 |
S1T (sarcoendoplasmic reticulum Ca2+-ATPase 1) S1T(肌内质网Ca 2+ -ATP酶1) |
HeLa cells 海拉细胞 | Leads to Ca2+ transport to mitochondria by increasing the number of EMCSs and inhibiting mitochondrial mobilization under ER stress conditions 通过增加 EMCS 的数量并抑制 ER 应激条件下的线粒体动员,导致 Ca 2+转运至线粒体 |
TOM70 (mitochondrial translocase of the outer membrane 70) TOM70(外膜线粒体转位酶70) |
Mouse, HeLa cells 小鼠、HeLa 细胞 | Forms a cluster that contacts the ER and recruits IP3R3 to EMCSs via a physical interaction 形成一个联系 ER 的集群,并通过物理交互将 IP3R3 招募到 EMCS |
As Ca2+ participates in diverse cellular processes, disrupted homeostasis and improper regulation of Ca2+ dynamics in MAMs can negatively affect cellular function. The influx of Ca2+ into mitochondria is essential for bioenergetics because several intramitochondrial enzymes associated with glycolysis and the tricarboxylic acid cycle are activated in a calcium-dependent manner46. The lack of constitutive Ca2+ influx through IP3 reduces the enzymatic activity of pyruvate dehydrogenase and thus the production of adenosine triphosphate (ATP), resulting in the activation of autophagy via the AMPK pathway47. Translocase of mitochondrial outer membrane 70 (TOM70) also affects constitutive Ca2+ shuttling by mediating the linkage between IP3R3 and VDAC, and the depletion of TOM70 results in impaired mitochondrial respiration48.
由于 Ca 2+参与多种细胞过程,MAM 中体内平衡的破坏和 Ca 2+动力学的不当调节会对细胞功能产生负面影响。 Ca 2+流入线粒体对于生物能学至关重要,因为几种与糖酵解和三羧酸循环相关的线粒体内酶以钙依赖性方式被激活46 。缺乏通过 IP3 的组成型 Ca 2+流入会降低丙酮酸脱氢酶的酶活性,从而降低三磷酸腺苷 (ATP) 的产生,从而导致通过 AMPK 途径激活自噬47 。线粒体外膜转位酶 70 (TOM70) 还通过介导 IP3R3 和 VDAC 之间的连接来影响组成型 Ca 2+穿梭,TOM70 的耗竭会导致线粒体呼吸受损48 。
MAM proteins stimulate Ca2+-dependent apoptotic pathways. Ca2+ overload in the mitochondrial matrix increases mitochondrial permeability by opening mitochondrial permeability transition pores (mPTPs)49. One mechanism of permeability transition is Ca2+-inducible conformational alteration of F-ATP synthases that bind to and show activity toward mPTPs50. The opening of mPTPs disrupts the osmotic balance in mitochondria due to nonselective permeabilization, resulting in an influx of water that induces the release of caspase cofactors51. Furthermore, alterations in Ca2+ levels are closely associated with responses to multiple intracellular stresses, such as ER and oxidative stress.
MAM 蛋白刺激 Ca 2+依赖性细胞凋亡途径。线粒体基质中的 Ca 2+超载通过打开线粒体通透性转换孔 (mPTP) 来增加线粒体通透性49 。通透性转变的一种机制是 Ca 2+诱导的 F-ATP 合酶构象改变,该合酶结合 mPTP 并显示出对 mPTP 的活性50 。由于非选择性透化,mPTP 的开放破坏了线粒体的渗透平衡,导致水流入,诱导 caspase 辅助因子的释放51 。此外,Ca 2+水平的变化与多种细胞内应激(例如 ER 和氧化应激)的反应密切相关。
ER–mitochondria contacts modulate oxidative stress
ER-线粒体接触调节氧化应激
Oxidative stress results from an imbalance between the production and accumulation of reactive oxygen species (ROS) in cells and is a hallmark of the ability to detoxify or repair reactive products52. ROS are produced primarily in mitochondria and play important roles in cell growth, differentiation, and death53,54. Although low levels of ROS play an essential role in intracellular signaling and pathogen defense, elevated levels can have detrimental effects on cells, such as decreasing the efficiency of mitochondrial respiration and inducing oncogenic stress55. Imbalances in ROS accumulation can contribute to the development and progression of several diseases, including cancer, metabolic disorders, diabetes, and cardiovascular diseases56,57.
氧化应激是由细胞中活性氧 (ROS) 的产生和积累之间的不平衡引起的,是解毒或修复反应产物的能力的标志52 。 ROS 主要在线粒体中产生,在细胞生长、分化和死亡中发挥重要作用53 , 54 。尽管低水平的 ROS 在细胞内信号传导和病原体防御中发挥着重要作用,但水平升高会对细胞产生有害影响,例如降低线粒体呼吸效率并诱导致癌应激55 。 ROS 积累的不平衡可能会导致多种疾病的发生和进展,包括癌症、代谢紊乱、糖尿病和心血管疾病56 , 57 。
The ER and mitochondrial axes play essential roles in the detection of and response to stress conditions, including oxidative stress, and form interconnected networks58. Furthermore, the simultaneous induction of ER stress and overproduction of ROS in several diseases highlights the importance of this axis59. The roles of ROS-related MAM proteins, including endoplasmic reticulum oxidoreductase 1 (ERO1), Sig-1R, p66Shc, and MFN2, have been reported (Fig. 2).
ER 和线粒体轴在应激条件(包括氧化应激)的检测和响应中发挥重要作用,并形成互连网络58 。此外,在几种疾病中同时诱导 ER 应激和 ROS 过量产生凸显了该轴的重要性59 。 ROS 相关的 MAM 蛋白,包括内质网氧化还原酶 1 (ERO1)、Sig-1R、p66Shc 和 MFN2 的作用已有报道(图2 )。
ERO1 is located entirely on the MAMs close to the ER surface and is an essential factor in the ER oxidative folding mechanism through co-localization with protein disulfide isomerase (PDI)60. PDI catalyzes the formation of disulfide bonds in unfolded proteins during oxidative protein folding and is then converted to a reduced form61. Reduced PDI is subsequently oxidized by ERO1 to participate in the catalytic reaction cycle, where reduced ERO1 transfers electrons to an oxygen molecule via flavin adenine dinucleotide, releasing H2O260. ERO1α, an ERO1 isoform, is overexpressed in various cancers, and its expression is increased by chronic ER stress, resulting in excessive H2O2 production and an increased ROS burden62. ERO1 also affects ROS production by regulating other MAM proteins. Under stress conditions, ERO1 oxidizes IP3R1 and induces detachment of the disulfide isomerase–like protein ERp44 from IP3R163. ERp44 has an inhibitory effect on IP3R164, leading to massive influx of Ca2+ through IP3R, which ultimately results in upregulated mitochondrial metabolism and excessive ROS production65,66.
ERO1 完全位于靠近 ER 表面的 MAM 上,通过与蛋白质二硫键异构酶 (PDI) 共定位,成为 ER 氧化折叠机制的重要因素60 。 PDI 在蛋白质氧化折叠过程中催化未折叠蛋白质中二硫键的形成,然后转化为还原形式61 。还原型PDI随后被ERO1氧化,参与催化反应循环,其中还原型ERO1通过黄素腺嘌呤二核苷酸将电子转移到氧分子,释放H 2 O 2 60 。 ERO1α 是一种 ERO1 亚型,在多种癌症中过度表达,并且其表达因慢性 ER 应激而增加,导致 H 2 O 2产生过多和 ROS 负担增加62 。 ERO1 还通过调节其他 MAM 蛋白来影响 ROS 的产生。在应激条件下,ERO1 氧化 IP3R1 并诱导二硫键异构酶样蛋白 ERp44 从 IP3R1 上分离63 。 ERp44 对 IP3R1 具有抑制作用64 ,导致 Ca 2+通过 IP3R 大量流入,最终导致线粒体代谢上调和 ROS 产生过多65 , 66 。
Sig-1R regulates Ca2+ homeostasis and is involved in ROS-related signaling pathways. Although the ROS-regulatory mechanisms of Sig-1R are not fully understood, previous studies have shown that Sig-1R knockdown leads to ROS accumulation67,68. Furthermore, some Sig-1R agonists exhibit antioxidant activity under pathological conditions69.
Sig-1R 调节 Ca 2+稳态并参与 ROS 相关信号通路。尽管 Sig-1R 的 ROS 调节机制尚不完全清楚,但先前的研究表明 Sig-1R 敲低会导致 ROS 积累67 , 68 。此外,一些 Sig-1R 激动剂在病理条件下表现出抗氧化活性69 。
p66Shc is located in MAMs, mitochondria, and the cytosol and tetramerizes in response to oxidative stress70. Under oxidative stress conditions, its Ser36 residue is phosphorylated by p38MAPK, ERK, and JNK1/2, and phosphorylation of other residues, namely, Ser54 and Thr386, occurs to prevent p66Shc degradation by ubiquitination71–73. Activated p66Shc translocates through MAMs into mitochondria, where it binds to cytochrome c to generate ROS and ultimately induce cell death74. The generation of ROS by activated p66Shc is supported by previous studies showing that both p66Shc knockout mice and cells exhibit reduced oxidative stress levels and a decreased incidence of diseases such as atherosclerosis75,76.
p66Shc 位于 MAM、线粒体和细胞质中,并响应氧化应激而四聚化70 。在氧化应激条件下,其 Ser36 残基被 p38MAPK、ERK 和 JNK1/2 磷酸化,并且其他残基(即 Ser54 和 Thr386)发生磷酸化,以防止 p66Shc 被泛素化降解71 – 73 。激活的 p66Shc 通过 MAM 易位到线粒体中,在线粒体中与细胞色素 c 结合产生 ROS 并最终诱导细胞死亡74 。先前的研究表明,p66Shc 敲除小鼠和细胞都表现出氧化应激水平降低和动脉粥样硬化等疾病发生率降低75 、 76 ,这些研究支持了激活的 p66Shc 产生 ROS 。
As previously described, both MFN1 and MFN2 are involved in the promotion of mitochondrial fusion. However, the fusion process, which relies primarily on MFN1 and MFN2, is speculated to have additional distinct functions77. The possible effects of MFN2 on ROS generation have been suggested to be due to other functions of MFN2. Munoz et al.78 reported the possible inhibitory effects of MFN2 on ROS production. MFN2 directly interacts with an ER stress branch, the pancreatic endoplasmic reticulum kinase (PERK) pathway, and inhibits ER stress pathways and ROS production. Other studies have shown that MFN2 overexpression activates the PERK/activating transcription factor 4 (ATF4) pathway and reduces ROS levels in cardiac fibroblasts79. However, a recent study showed that MFN2 facilitates the adaptation of macrophages to mitochondrial respiration and ROS generation in response to inflammatory stimuli80. Thus, further research is required to fully understand the different functions of MFN2 in different cell types and under specific stress conditions.
如前所述,MFN1 和 MFN2 都参与促进线粒体融合。然而,主要依赖于 MFN1 和 MFN2 的融合过程被推测具有额外的不同功能77 。 MFN2 对 ROS 生成的可能影响被认为是由于 MFN2 的其他功能。穆尼奥斯等人。 78报告了 MFN2 对 ROS 产生可能的抑制作用。 MFN2 直接与 ER 应激分支、胰腺内质网激酶 (PERK) 通路相互作用,并抑制 ER 应激通路和 ROS 产生。其他研究表明,MFN2 过表达会激活 PERK/激活转录因子 4 (ATF4) 通路并降低心脏成纤维细胞中的 ROS 水平79 。然而,最近的一项研究表明,MFN2 促进巨噬细胞适应线粒体呼吸和 ROS 生成,以响应炎症刺激80 。因此,需要进一步的研究来充分了解 MFN2 在不同细胞类型和特定应激条件下的不同功能。
Interaction between ER stress and the ER–mitochondria axis
内质网应激与内质网-线粒体轴之间的相互作用
Protein folding is the main function of the ER. Various conditions, such as disruption of Ca2+ homeostasis, inhibition of degradation of unfolded proteins due to proteasome blockade, and genetic mutations, can cause the accumulation of unfolded proteins81. Under these stress conditions, the unfolded protein response (UPR) is activated by three ER transmembrane proteins: activating transcription factor 6 (ATF6), inositol-requiring enzyme 1α (IRE1α), and PERK82. Under normal conditions, the ER chaperone GRP78/BiP binds to the ER lumen region of these transmembrane proteins and inhibits their activity. However, under stress conditions, GRP78 binds to misfolded proteins and induces the activation of these three transmembrane proteins83.
蛋白质折叠是内质网的主要功能。各种条件,例如Ca 2+稳态的破坏、由于蛋白酶体阻断而抑制未折叠蛋白的降解以及基因突变,都可能导致未折叠蛋白的积累81 。在这些应激条件下,未折叠蛋白反应 (UPR) 由三种 ER 跨膜蛋白激活:激活转录因子 6 (ATF6)、肌醇需求酶 1α (IRE1α) 和 PERK 82 。正常情况下,内质网伴侣 GRP78/BiP 与这些跨膜蛋白的内质网腔区域结合并抑制其活性。然而,在应激条件下,GRP78 与错误折叠的蛋白质结合并诱导这三种跨膜蛋白的激活83 。
In the ATF6 pathway of the ER stress response, sensors mediate the UPR, and ATF6 translocates to the Golgi complex after GRP78 is released. ATF6 is first cleaved by site-1 protease, and one half remains at the NH2-terminus before being cleaved by site-2 protease84. Regarding the IRE pathway, GRP78 is normally bound to IRE1α or its homolog, IRE1p, and maintains its inactivation. When GRP78 dissociates from IRE1 in ER-stressed cells, IRE1 is phosphorylated and dimerizes85. Finally, activated PERK phosphorylates eIF2α and further increases the translation of selected mRNAs, including ATF4, which then promotes the expression of transcription factors, such as C/EBP homologous protein (CHOP), leading to growth arrest and DNA damage86. CHOP overexpression causes apoptosis by translocating B-cell lymphoma 2 (BCL2)-associated X (a proapoptotic protein) to mitochondria and decreasing the expression of BCL2 (an antiapoptotic protein)87.
在内质网应激反应的 ATF6 通路中,传感器介导 UPR,GRP78 释放后 ATF6 易位至高尔基复合体。 ATF6 首先被位点 1 蛋白酶切割,一半保留在 NH 2 -末端,然后被位点 2 蛋白酶切割84 。关于 IRE 通路,GRP78 通常与 IRE1α 或其同源物 IRE1p 结合,并维持其失活状态。当 GRP78 在内质网应激细胞中与 IRE1 解离时,IRE1 被磷酸化并二聚化85 。最后,激活的 PERK 磷酸化 eIF2α 并进一步增加选定 mRNA(包括 ATF4)的翻译,然后促进转录因子(如 C/EBP 同源蛋白 (CHOP))的表达,导致生长停滞和 DNA 损伤86 。 CHOP 过表达通过将 B 细胞淋巴瘤 2 (BCL2) 相关 X(一种促凋亡蛋白)易位至线粒体并降低 BCL2(一种抗凋亡蛋白)的表达来引起细胞凋亡87 。
The associations between MAM components and ER stress have been widely reported (Table 2), and some UPR-related proteins also function as MAM components. The interaction between PERK and MFN2 is a representative example of the UPR-related MAM pathway. Additionally, some MAM proteins are regulated by ER stress; for instance, Sig-1R is transcriptionally upregulated via the PERK/eIF2α/ATF4 pathway88, while another MAM protein, Rab32, is upregulated via the UPR pathway. Rab32 belongs to the Ras-like small GTPase family and is involved in mitochondrial fission via interaction with DRP189. In SH-SY5Y cells, Rab32 expression is elevated upon induction of ER stress (thapsigargin treatment), leading to mitochondrial dysfunction and neuronal death90. Furthermore, the ER chaperone GRP78 binds to IP3R1 during the ER stress response, releasing Ca2+ for influx into mitochondria and inducing cell death due to mitochondrial dysfunction91.
MAM 成分与 ER 应激之间的关联已被广泛报道(表2 ),一些 UPR 相关蛋白也起到 MAM 成分的作用。 PERK 和 MFN2 之间的相互作用是 UPR 相关 MAM 途径的代表性例子。此外,一些 MAM 蛋白受 ER 应激调节;例如,Sig-1R 通过 PERK/eIF2α/ATF4 途径转录上调88 ,而另一种 MAM 蛋白 Rab32 通过 UPR 途径上调。 Rab32 属于 Ras 样小 GTP 酶家族,通过与 DRP1 相互作用参与线粒体裂变89 。在 SH-SY5Y 细胞中,Rab32 表达在诱导 ER 应激(毒胡萝卜素处理)后升高,导致线粒体功能障碍和神经元死亡90 。此外,ER 伴侣 GRP78 在 ER 应激反应期间与 IP3R1 结合,释放 Ca 2+流入线粒体并诱导由于线粒体功能障碍而导致的细胞死亡91 。
Table 2. 表 2.
Complex Name 复合名称 | Cells 细胞 | Functional of mechanisms 机制的功能 |
---|---|---|
IP3R1-GRP75-VDAC complex IP3R1-GRP75-VDAC 复合体 | pLE and pTr pLE 和 pTr | Induces apoptosis through mitochondrial dysfunction and ER stress via the IP3R/GRP75/VDAC1-MCU axis 通过 IP3R/GRP75/VDAC1-MCU 轴通过线粒体功能障碍和 ER 应激诱导细胞凋亡 |
ES2 and OV90 ES2 和 OV90 | Induces ER stress with activation of the UPR due to increases in cytosolic and mitochondrial calcium 由于细胞质和线粒体钙的增加,UPR 激活,诱导 ER 应激 |
|
BMECs 骨髓内皮细胞 | Induces ER stress and mitochondrial oxidative damage via the IP3R/GRP75/VDAC1-MCU axis 通过 IP3R/GRP75/VDAC1-MCU 轴诱导 ER 应激和线粒体氧化损伤 |
|
VAPB-PTPIP51 complex VAPB-PTPIP51复合物 | NSC34 | Induces inhibition of IRE1/XBP1 due to VAPB loss under ER stress conditions 在内质网应激条件下由于 VAPB 损失而诱导 IRE1/XBP1 的抑制 |
HEK293 and CV1 HEK293 和 CV1 | Induces Ca2+ regulation due to an interaction with PTPIP51 via VAPB-induced ER stress 通过 VAPB 诱导的 ER 应激与 PTPIP51 相互作用,诱导 Ca 2+调节 |
|
MFN2-MFN2 complex MFN2-MFN2复合物 | ES2 and OV90 ES2 和 OV90 | Induces inhibition of cell growth under ER and mitochondrial stress conditions 在内质网和线粒体应激条件下诱导细胞生长抑制 |
Sig-1R | HEK293 | Induces apoptosis via upregulation of the PERK/eIF2α/ATF4 pathway under ER stress conditions 在内质网应激条件下通过上调 PERK/eIF2α/ATF4 通路诱导细胞凋亡 |
Rab32 拉布32 | SH-SY5Y | Induces mitochondrial dysfunction and cell death with upregulation of GRP75 and MFN2 under ER stress conditions 在内质网应激条件下上调 GRP75 和 MFN2,诱导线粒体功能障碍和细胞死亡 |
Further evidence has also revealed that several MAM proteins affect UPR pathways. The ER protein VAPB is an important protein involved in UPR activity, and VABP loss inhibits IRE1/XBP1 activity in response to ER stress92. Furthermore, VAPB interacts with ATF6 in response to ER stress, and the terminal domain of ATF6 senses protein accumulation in the ER lumen. VAPB, with no luminal structure, is not directly regulated by ATF6 activation but is indirectly inhibited93. VAPB-induced ER stress has been implicated in inducing mitochondrial dysfunction by releasing Ca2+ through interactions with PTPIP51 in the mitochondrial membrane23.
进一步的证据还表明,几种 MAM 蛋白影响 UPR 途径。 ER 蛋白 VAPB 是参与 UPR 活性的重要蛋白,VABP 损失会抑制 IRE1/XBP1 响应 ER 应激的活性92 。此外,VAPB 与 ATF6 相互作用以响应 ER 应激,并且 ATF6 的末端结构域感知 ER 腔中的蛋白质积累。 VAPB 没有管腔结构,不会直接受 ATF6 激活的调节,而是会被间接抑制93 。 VAPB 诱导的 ER 应激通过与线粒体膜中的 PTPIP51 相互作用释放 Ca 2+来诱导线粒体功能障碍23 。
Characteristics and diagnostic role of ER–mitochondria contact sites in cancers
癌症中内质网-线粒体接触位点的特征和诊断作用
Cancer cells require a substantial amount of energy for their rapid proliferation and acquisition of malignant phenotypes and use various methods, such as increases in glucose uptake and glycolytic activity (a phenomenon known as the Warburg effect), lipid synthesis and lipolysis, and modulation of Ca2+ signaling, to meet these requirements94–96. Therefore, MAMs play important roles in cancer cell function and metabolism, as they regulate the aforementioned pathways (Fig. 3).
癌细胞需要大量的能量来快速增殖和获得恶性表型,并使用各种方法,例如增加葡萄糖摄取和糖酵解活性(一种称为瓦尔堡效应的现象)、脂质合成和脂肪分解以及 Ca 的调节2+信令,以满足这些要求94 – 96 。因此,MAM在癌细胞功能和代谢中发挥着重要作用,因为它们调节上述途径(图3 )。
The regulation of Ca2+ signaling is crucial in cancers, as it is involved in cancer progression, epithelial-to-mesenchymal transition, invasion, and resistance to apoptosis97. Therefore, Ca2+-regulating proteins in MAMs play various roles in cancer development (Table 3). The IP3R-GRP75-VDAC-MCU complex, which plays an important role in Ca2+ transport, is regulated by oncoproteins such as PTEN, BRCA1, and BCL298. In MAMs, PTEN binds to IP3R and prevents its degradation, thereby promoting Ca2+ transport to mitochondria, which is important for apoptosis98,99. However, in various cancers, PTEN loses functionality and triggers inappropriate Ca2+ transport, leading to apoptosis resistance100,101. BCL2, another oncoprotein in MAMs, interacts with IP3R and VDAC and prevents the translocation of Ca2+ from the ER to mitochondria. Furthermore, the interaction between BCL2 and VDAC1 interferes with the export of cytochrome c from mitochondria and thus hinders apoptosis98,102. Therefore, BCL2 overexpression in cancers results in resistance to apoptosis.
Ca 2+信号传导的调节在癌症中至关重要,因为它参与癌症进展、上皮间质转化、侵袭和细胞凋亡抵抗97 。因此,MAM中的Ca 2+调节蛋白在癌症发展中发挥着多种作用(表3 )。 IP3R-GRP75-VDAC-MCU 复合物在 Ca 2+转运中发挥重要作用,受 PTEN、BRCA1 和 BCL2 等癌蛋白的调节98 。在 MAM 中,PTEN 与 IP3R 结合并防止其降解,从而促进 Ca 2+转运至线粒体,这对于细胞凋亡很重要98 , 99 。然而,在各种癌症中,PTEN 失去功能并触发不适当的 Ca 2+转运,导致细胞凋亡抵抗100 , 101 。 BCL2 是 MAM 中的另一种癌蛋白,与 IP3R 和 VDAC 相互作用,并阻止 Ca 2+从 ER 易位至线粒体。此外,BCL2 和 VDAC1 之间的相互作用会干扰细胞色素 c 从线粒体的输出,从而阻碍细胞凋亡98 , 102 。因此,BCL2在癌症中的过度表达会导致细胞凋亡抵抗。
Table 3. 表 3.
Treatment approach 治疗方法 | Target protein 目标蛋白 | Function 功能 | Therapeutic 治疗性 | Cancer 癌症 |
---|---|---|---|---|
Inducing apoptosis through Ca2+ signaling 通过 Ca 2+信号传导诱导细胞凋亡 |
IP3R | Increase IP3R-mediated Ca2+ influx into mitochondria 增加 IP3R 介导的 Ca 2+流入线粒体 |
Cisplatin 顺铂 | -Ovarian cancer -卵巢癌 |
P53 | Increase p53 signaling related to SERCA activity and increase Ca2+ transfer to mitochondria, inducing apoptosis 增加与 SERCA 活性相关的 p53 信号传导,增加 Ca 2+向线粒体的转移,诱导细胞凋亡 |
Adriamycin 阿霉素 | Almost all cancers 几乎所有癌症 | |
ATP synthase ATP合成酶 | Inhibit ATP synthase, leading to SERCA activity and resulting in mitochondrial apoptosis 抑制 ATP 合成酶,导致 SERCA 活性并导致线粒体凋亡 |
Resveratrol 白藜芦醇 | Colorectal cancers 结直肠癌 | |
SERCA | Inhibit SERCA, which increases intracellular Ca2+, inducing apoptosis 抑制 SERCA,增加细胞内 Ca 2+ ,诱导细胞凋亡 |
Mipsagargin 米普萨加金 | Prostate, breast and bladder cancers 前列腺癌、乳腺癌和膀胱癌 |
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BCL2 | Disrupt the interaction between BCL2 and IP3R, inducing Ca2+ release and apoptosis 破坏 BCL2 和 IP3R 之间的相互作用,诱导 Ca 2+释放和细胞凋亡 |
BIRD2 | Various cancers including large B-cell lymphoma, chronic lymphocytic leukemia 各种癌症,包括大 B 细胞淋巴瘤、慢性淋巴细胞白血病 |
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Inducing apoptosis through lipid metabolism 通过脂质代谢诱导细胞凋亡 |
GRP78 | Inhibit GRP78 and induce ER stress in cancer cells 抑制 GRP78 并诱导癌细胞内质网应激 |
HA-15 | Human adrenocortical H295R cells 人肾上腺皮质H295R细胞 |
ACAT-1 | Inhibit ACAT-1, causing the accumulation of free cholesterol and fatty acids, thus inducing ER stress 抑制ACAT-1,导致游离胆固醇和脂肪酸积累,从而诱发内质网应激 |
Mitotane 米托丹 | Adrenocortical carcinoma 肾上腺皮质癌 | |
Increasing sensitivity to anticancer 提高抗癌敏感性 |
GRP75 | Knock down GRP75, increasing cisplatin sensitivity 敲低 GRP75,增加顺铂敏感性 |
- | Ovarian cancer 卵巢癌 |
BCL2 | Inhibit BCL2, increasing intracellular Ca2+ levels 抑制 BCL2,增加细胞内 Ca 2+水平 |
ABT737 | Ovarian cancer 卵巢癌 | |
Reducing metastasis 减少转移 | FUNDC1 | Inhibit FUNDC1, which regulates mitophagy and stimulates the proliferation and invasion of cancer cells 抑制 FUNDC1,它调节线粒体自噬并刺激癌细胞的增殖和侵袭 |
- | Breast cancer 乳腺癌 |
MCU | Inhibit MCU, leading to ROS suppression and HIF-1α downregulation, thus resulting in inhibition of tumor progression and metastasis 抑制MCU,导致ROS抑制和HIF-1α下调,从而抑制肿瘤进展和转移 |
- | Breast, ovarian, prostate, and colorectal cancer 乳腺癌、卵巢癌、前列腺癌和结直肠癌 |
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Increasing immune cell accessibility 增加免疫细胞的可及性 |
- | Change glycan expression by modulating ER–mitochondria interactions 通过调节 ER-线粒体相互作用来改变聚糖表达 |
- | Glioblastoma 胶质母细胞瘤 |
BRCA1-associated protein 1 (BAP1), a tumor suppressor protein in MAMs, facilitates Ca2+ influx into mitochondria by interacting with IP3R103. Abnormalities in the function of BAP1 can induce inappropriate Ca2+ influx into mitochondria, which may affect the regulation of apoptosis and lead to carcinogenesis104. Mutations in BAP1 have been observed in various cancers, including renal cell carcinoma, cutaneous melanoma, and uveal melanoma104. GRP75 also plays an important role in the regulation of Ca2+ homeostasis2. Transglutaminase type 2 modulates GRP75 function by binding to GRP75 and increasing Ca2+ flux between the ER and mitochondria, which affects cancer growth and metastasis. Upregulation of transglutaminase type 2 is a hallmark of breast cancer105,106. Additionally, TOM70, a protein that links IP3R3 to VDAC, exhibits notably high expression levels in breast cancer cells, and its potential as a therapeutic target has been duly recognized in previous studies48,107.
BRCA1 相关蛋白 1 (BAP1) 是 MAM 中的一种肿瘤抑制蛋白,通过与 IP3R 相互作用促进 Ca 2+流入线粒体103 。 BAP1功能异常可诱导Ca 2+不适当地流入线粒体,从而影响细胞凋亡的调节并导致癌变104 。 BAP1 突变已在多种癌症中观察到,包括肾细胞癌、皮肤黑色素瘤和葡萄膜黑色素瘤104 。 GRP75 在 Ca 2+稳态的调节中也发挥着重要作用2 。 2 型转谷氨酰胺酶通过与 GRP75 结合并增加 ER 和线粒体之间的 Ca 2+通量来调节 GRP75 功能,从而影响癌症生长和转移。 2 型转谷氨酰胺酶的上调是乳腺癌的标志105 , 106 。此外,TOM70(一种将 IP3R3 与 VDAC 连接的蛋白质)在乳腺癌细胞中表现出显着高的表达水平,其作为治疗靶点的潜力已在之前的研究中得到充分认识48 , 107 。
In addition to its proapoptotic role in mitochondria, Ca2+ is important for energy production, progression, and metastasis in cancer108,109. Ca2+ influx into mitochondria mediated by MCU promotes mitochondrial biogenesis and colon cancer proliferation108, and impairment of Ca2+ uptake by MCU knockdown inhibits the proliferation of embryonal rhabdomyosarcoma110. Other types of cancers with high MCU expression include prostate, ovarian, and breast cancers, indicating the diagnostic utility of MCU expression in cancer111. Moreover, PDZD8, another Ca2+-regulating protein in MAMs, was found to exhibit increased expression levels in stomach cancer tissue compared with normal tissue and is involved in the proliferation and metastasis of stomach cancer112.
除了其在线粒体中的促凋亡作用之外,Ca 2+对于癌症的能量产生、进展和转移也很重要108 , 109 。 MCU 介导的 Ca 2+流入线粒体可促进线粒体生物合成和结肠癌增殖108 ,而 MCU 敲低导致的 Ca 2+摄取受损可抑制胚胎横纹肌肉瘤的增殖110 。其他具有高 MCU 表达的癌症类型包括前列腺癌、卵巢癌和乳腺癌,这表明 MCU 表达在癌症中的诊断效用111 。此外,MAM中的另一种Ca 2+调节蛋白PDZD8被发现在胃癌组织中与正常组织相比表现出表达水平升高,并且参与胃癌的增殖和转移112 。
Although research on the exact role of ROS in cancers is still underway, ROS are known to be involved in cancer progression and metastasis98. Several MAM proteins, including p66hsc, are regulated by ROS, and p66hsc and the oncoprotein p53 regulate each other113. Furthermore, p66hsc can be activated by steroid hormones, and activated p66hsc interacts with cytochrome c to increase ROS production. These alterations, including oxidative stress, have been reported to result in poor prognosis in patients with prostate cancer72,114–116. These characteristics of p66hsc have also been observed in other cancers, including breast and lung cancers, indicating its potential as a diagnostic and therapeutic target117–119. Furthermore, ERO1, which controls ROS production through the regulation of MAM proteins, is overexpressed in cholangiocarcinoma and is involved in proliferation and metastasis, leading to poor prognosis in patients120. Notably, ERO1 is also overexpressed in various other cancers, including breast cancer, lung cancer, and hepatocellular carcinoma, in which it ultimately results in poor prognosis121–123.
尽管关于 ROS 在癌症中的确切作用的研究仍在进行中,但已知 ROS 参与癌症进展和转移98 。包括 p66hsc 在内的多种 MAM 蛋白受 ROS 调节,并且 p66hsc 和癌蛋白 p53 相互调节113 。此外,p66hsc可以被类固醇激素激活,激活的p66hsc与细胞色素c相互作用以增加ROS的产生。据报道,这些改变(包括氧化应激)会导致前列腺癌患者预后不良72 , 114 – 116 。 p66hsc 的这些特征也在其他癌症(包括乳腺癌和肺癌)中观察到,表明其作为诊断和治疗靶点的潜力117 – 119 。此外,ERO1通过调节MAM蛋白来控制ROS的产生,在胆管癌中过度表达,并参与增殖和转移,导致患者预后不良120 。值得注意的是,ERO1 在多种其他癌症中也过度表达,包括乳腺癌、肺癌和肝细胞癌,最终导致预后不良121 – 123 。
Activated lipid metabolism and the accumulation of lipid droplets are hallmarks of various cancer cells95. Elevated lipid levels in cancer cells promote proliferation and serve as energy reserves and messengers in oncogenic pathways95,124. Furthermore, various enzymes involved in lipid synthesis are upregulated in various cancers, including lung, ovarian, and prostate cancers95,125,126. Various enzymes involved in lipid synthesis, such as fatty acid CoA ligase, which catalyzes the ligation of triacylglycerols and ceramide, and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1), which catalyzes the synthesis of cholesterol, are mainly located in MAMs98,127,128. Therefore, alterations in the expression of these enzymes in MAMs are strongly associated with cancer. For example, after passing through mitochondria, ceramide plays an important role as an apoptosis inducer and can inhibit cancer growth and cell death129,130. Cholesterol metabolism is strongly associated with cancer. ACAT-1 in MAMs converts cholesterol to cholesteryl esters, which accumulate in the lipid droplets of cancer cells98,131. These accumulated cholesteryl esters have a considerable impact on the proliferation and metastasis of cancer cells132. Caveolin-1, located in MAMs, is involved in cholesterol efflux, and its overexpression has been identified in a variety of cancers, such as lung, liver, kidney, and colon cancers133. These expression patterns of caveolin-1 are closely related to cancer progression, metastasis, and drug resistance134–136. Therefore, various MAM proteins play major roles in cancer and can potentially be used in diagnosis and treatment. The association between ER stress and cancer has been established137. Sig-1R, a MAM protein regulated by ER stress, has been reported to be overexpressed in myelogenous leukemia and colon cancer138. This increased expression promotes angiogenesis and facilitates cancer cell migration, resulting in poor prognosis in patients. Consequently, Sig-1R is considered a promising therapeutic target138. Another MAM protein associated with ER stress, VAP-B, has been reported to play a key role in breast cancer progression, highlighting its potential as a diagnostic marker for this malignancy139.
激活的脂质代谢和脂滴的积累是各种癌细胞的标志95 。癌细胞中脂质水平升高会促进增殖并充当致癌途径中的能量储备和信使95 , 124 。此外,参与脂质合成的各种酶在各种癌症中上调,包括肺癌、卵巢癌和前列腺癌95 , 125 , 126 。参与脂质合成的各种酶,如催化三酰甘油和神经酰胺连接的脂肪酸CoA连接酶,以及催化胆固醇合成的酰基辅酶A:胆固醇酰基转移酶-1(ACAT-1),主要位于MAM 98、127、128 。因此,MAM 中这些酶表达的改变与癌症密切相关。例如,通过线粒体后,神经酰胺作为细胞凋亡诱导剂发挥着重要作用,可以抑制癌症生长和细胞死亡129 、 130 。胆固醇代谢与癌症密切相关。 MAM 中的 ACAT-1 将胆固醇转化为胆固醇酯,胆固醇酯积聚在癌细胞的脂滴中98 、 131 。这些积累的胆固醇酯对癌细胞的增殖和转移有相当大的影响132 。 Caveolin-1 位于 MAM 中,参与胆固醇流出,其过度表达已在多种癌症中发现,如肺癌、肝癌、肾癌和结肠癌133 。 Caveolin-1 的这些表达模式与癌症进展、转移和耐药性密切相关134 – 136 。因此,各种MAM蛋白在癌症中发挥着重要作用,并有可能用于诊断和治疗。 ER 应激与癌症之间的关联已被确定137 。 Sig-1R 是一种受 ER 应激调节的 MAM 蛋白,据报道在骨髓性白血病和结肠癌中过度表达138 。这种表达增加会促进血管生成并促进癌细胞迁移,导致患者预后不良。因此,Sig-1R 被认为是一个有前途的治疗靶点138 。据报道,另一种与 ER 应激相关的 MAM 蛋白 VAP-B 在乳腺癌进展中发挥着关键作用,凸显了其作为这种恶性肿瘤的诊断标志物的潜力139 。
The ER–mitochondrial axis as a therapeutic target
ER-线粒体轴作为治疗靶点
Targeting Ca2+ signaling
靶向 Ca 2+信号传导
The characteristic functions of MAMs, including those in Ca2+ and ROS signaling, lipid metabolism, autophagy, and mitochondrial fission, enable their use as diagnostic markers and therapeutic targets for cancer (Fig. 3). Different methods can be used to trigger cancer cell apoptosis by promoting Ca2+ transport through modulation of MAM proteins. One of the most widely used anticancer drugs, cisplatin, is used to treat various cancers, including ovarian, breast, lung, and bladder cancers140. In ovarian cancer (SKOV3) cells, cisplatin promotes Ca2+ translocation from the ER to mitochondria and cytosol, causing ER stress-mediated apoptosis141. Other cancer therapeutics, such as adriamycin and mipsagargin, target Ca2+ signaling. In MAMs, p53 regulates the activity of SERCA by binding to it, leading to Ca2+ influx into the ER and resulting in increased apoptosis142. p53 mutations have been detected in various types of cancers, and adriamycin can increase p53 levels in MAMs, which promotes Ca2+ signaling and apoptosis in cancer cells through the activation of SERCA111,142,143. Mipsagargin inhibits SERCA function, resulting in an increase in intracellular Ca2+, which induces apoptosis in cancer cells144. Another component of the Ca2+ transport complex, VDAC, can potentially serve as a biomarker and therapeutic target for breast cancer, as its overexpression was detected in a previous study145. Furthermore, VDAC1 inhibition by siRNA induces cancer cell apoptosis, suggesting that siRNAs could be a target for cancer therapy146,147. Previous studies have shown that PDZD8, which is highly expressed in stomach cancer and is involved in cancer cell proliferation and metastasis, can also be used as a therapeutic target112. Notably, sunitinib, a kinase inhibitor, attenuates the proliferation of stomach cancer cells, as demonstrated in the human gastric cancer cell lines TMK1 and MKN74, by decreasing the PDZD8 protein level112.
MAM 的特征功能,包括 Ca 2+和 ROS 信号传导、脂质代谢、自噬和线粒体裂变中的功能,使其能够用作癌症的诊断标记物和治疗靶点(图3 )。可以使用不同的方法通过调节 MAM 蛋白促进 Ca 2+转运来触发癌细胞凋亡。顺铂是最广泛使用的抗癌药物之一,用于治疗各种癌症,包括卵巢癌、乳腺癌、肺癌和膀胱癌140 。在卵巢癌 (SKOV3) 细胞中,顺铂促进 Ca 2+从 ER 易位至线粒体和细胞质,导致 ER 应激介导的细胞凋亡141 。其他癌症治疗药物,例如阿霉素和米普萨加根,以 Ca 2+信号传导为目标。在 MAM 中,p53 通过与 SERCA 结合来调节 SERCA 的活性,导致 Ca 2+流入 ER 并导致细胞凋亡增加142 。 p53 突变已在多种类型的癌症中检测到,阿霉素可以增加 MAM 中的 p53 水平,从而通过激活 SERCA 111 , 142 , 143促进癌细胞中的 Ca 2+信号传导和细胞凋亡。 Mipsagargin 抑制 SERCA 功能,导致细胞内 Ca 2+增加,从而诱导癌细胞凋亡144 。 Ca 2+转运复合物的另一个组成部分 VDAC 可以作为乳腺癌的生物标志物和治疗靶点,因为在之前的研究中检测到其过度表达145 。 此外,siRNA 抑制 VDAC1 会诱导癌细胞凋亡,表明 siRNA 可能成为癌症治疗的靶点146 , 147 。先前的研究表明,PDZD8在胃癌中高表达并参与癌细胞的增殖和转移,也可以作为治疗靶点112 。值得注意的是,舒尼替尼(一种激酶抑制剂)通过降低 PDZD8 蛋白水平来减弱胃癌细胞的增殖,如人胃癌细胞系 TMK1 和 MKN74 中所证明的那样112 。
Targeting lipid metabolism and ER stress
针对脂质代谢和内质网应激
Targeting the lipid metabolism-related functions of MAMs could aid in cancer treatment. For example, mitotane, which targets ACAT-1, converts cholesterol to CE and causes lipid droplet formation in various cancers148. In adrenocortical carcinoma, mitotane-induced ACAT-1 suppression induces free cholesterol and fatty acid accumulation in the ER, leading to apoptosis111,148,149. Modulation of ER stress also constitutes a potential therapeutic approach for cancer. In prostate cancer, corosolic acid modulates IRE1 and PERK signaling and induces ER stress, which promotes apoptosis and inhibits cell proliferation150. In hepatocarcinoma, 20(S)-protopanaxadiol can increase UPR activity and enhance the ER stress response by phosphorylating components of the PERK cascade, subsequently leading to increases in the expression of associated genes151. Moreover, previous studies have shown that panaxydol induces Ca2+ release from the ER through IP3R and activates the JNK pathway, causing ER stress, which is mediated by PERK152,153. These effects trigger apoptosis in renal carcinoma and prostate cancer cells152,153. Evodiamine is another therapeutic candidate that affects the JNK and PERK pathways. By modulating both pathways, evodiamine can induce apoptosis in ovarian cancer cells and reduce the extent of metastasis in colon cancer153–155.
针对 MAM 的脂质代谢相关功能可能有助于癌症治疗。例如,靶向 ACAT-1 的米托坦 (mitotane) 将胆固醇转化为 CE,并在各种癌症中引起脂滴形成148 。在肾上腺皮质癌中,米托坦诱导的 ACAT-1 抑制会诱导内质网中游离胆固醇和脂肪酸的积累,导致细胞凋亡111 , 148 , 149 。内质网应激的调节也构成了一种潜在的癌症治疗方法。在前列腺癌中,科罗索酸调节 IRE1 和 PERK 信号传导并诱导 ER 应激,从而促进细胞凋亡并抑制细胞增殖150 。在肝癌中,20(S)-原人参二醇可以通过磷酸化 PERK 级联的成分来增加 UPR 活性并增强 ER 应激反应,随后导致相关基因表达增加151 。此外,之前的研究表明,人参醇通过IP3R诱导内质网Ca 2+释放,并激活JNK通路,引起内质网应激,这是由PERK 152 , 153介导的。这些效应触发肾癌和前列腺癌细胞的细胞凋亡152、153 。吴茱萸碱是另一种影响 JNK 和 PERK 通路的候选治疗药物。通过调节这两种途径,吴茱萸碱可以诱导卵巢癌细胞凋亡并减少结肠癌的转移程度153 – 155 。
Increasing the sensitivity of cancer cells to chemotherapeutic compounds
增加癌细胞对化疗化合物的敏感性
Repeated use of chemotherapeutic drugs can result in resistance to them; therefore, other MAM proteins can be targeted to reduce this resistance. For example, cisplatin is widely used to treat ovarian cancer; however, its long-term use can induce cisplatin resistance in ovarian cancer ce