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. 2023 Jun;37(6):758–763. [Article in Chinese] doi: 10.7507/1002-1892.202302056

视神经萎缩因子1介导的线粒体动力学在骨骼系统疾病中的研究进展

Research progress of optic atrophy 1-mediated mitochondrial dynamics in skeletal system diseases

Kaibo SUN 1, Yuangang WU 1, Yi ZENG 1, Mingyang LI 1, Limin WU 1, Bin SHEN 1,*
PMCID: PMC10277243  PMID: 37331956

Abstract

Objective

To review the research progress of mitochondrial dynamics mediated by optic atrophy 1 (OPA1) in skeletal system diseases.

Methods

The literatures about OPA1-mediated mitochondrial dynamics in recent years were reviewed, and the bioactive ingredients and drugs for the treatment of skeletal system diseases were summarized, which provided a new idea for the treatment of osteoarthritis.

Results

OPA1 is a key factor involved in mitochondrial dynamics and energetics and in maintaining the stability of the mitochondrial genome. Accumulating evidence indicates that OPA1-mediated mitochondrial dynamics plays an important role in the regulation of skeletal system diseases such as osteoarthritis, osteoporosis, and osteosarcoma.

Conclusion

OPA1-mediated mitochondrial dynamics provides an important theoretical basis for the prevention and treatment of skeletal system diseases.

Keywords: Mitochondrial quality control, mitochondrial dynamics, optic atrophy 1, disorder of skeletal system

线粒体是细胞中的“能量工厂”，产生并供应各种细胞代谢所需的能量；同时，线粒体也参与了多种细胞应激反应，例如自噬和凋亡等重要过程[1]。Youle等提出了“线粒体质量控制”的概念，即通过调节线粒体形态和数量，进而维持线粒体网络系统功能稳定，这是细胞应对应激反应的关键机制[2]。

线粒体质量控制整合了多种生物过程，包括线粒体氧化还原、线粒体生物发生、线粒体动力学和线粒体自噬[3-4]。线粒体自噬可消除受损线粒体，而线粒体生物发生则通过合成新的线粒体，使得线粒体持续更新，最终维持线粒体的稳态[5-6]。线粒体动力学包括线粒体膜电位、线粒体形态变化、线粒体运动以及线粒体的融合与分裂等过程，通过线粒体的融合和分裂可维持其形态和功能的动态平衡。通过选择性地融合健康和轻微受损的线粒体，稀释受损线粒体中的毒性超氧化物和突变线粒体基因组，以达到线粒体生化性质和遗传物质的同质性；同时，线粒体分裂可分离线粒体受损组件，最终将其通过蛋白水解系统被溶酶体降解[7-8]。

视神经萎缩因子1（optic atrophy 1，OPA1）是线粒体动力学的关键参与者，与其他融合蛋白分子如线粒体融合蛋白1（mitofusin 1，MFN1）和线粒体融合蛋白2（mitofusin 2，MFN2）密切合作，介导线粒体融合过程。OPA1参与线粒体内膜融合，而MFN1、2则参与线粒体外膜融合。已有研究表明沉默线粒体融合蛋白OPA1和MFN1、2表达会促进细胞凋亡[9]；而OPA1和MFN2过表达则会逆转线粒体融合受阻过程，进而维持线粒体稳态和细胞功能[10]。OPA1还可与裂变蛋白分子如动力相关蛋白1（dynamin-related protein 1，DRP1）和线粒体裂变蛋白1（mitochondrial fission 1 protein，FIS1）直接相互作用，并参与线粒体裂变过程[11]。鉴于此，本文就OPA1的主要生物功能及其介导的线粒体动力学在骨骼系统疾病调控中的作用机制进行阐述，为骨骼系统疾病的治疗提供理论依据。

1. OPA1生物结构和功能

1.1. OPA1的生物结构

OPA1基因定位于3q28，最早被确定为常染色体显性遗传性视神经萎缩发病的关键基因[12]。多数情况下，OPA1的致病性突变使得终止密码子提前出现，从而导致开放阅读框的截断，使得该等位基因功能丧失，最终使OPA1单倍剂量不足进而导致疾病发生[13]。

OPA1基因共有31个外显子，可通过不同位点的剪接并被编码多种亚型[14]。当OPA1前体进入线粒体膜后，线粒体加工肽酶对N末端区域的线粒体靶向序列切割产生了OPA1长型（long OPA1，L-OPA1），并锚定在线粒体内膜（inner mitochondrial membrane，IMM）上。随后，两种IMM肽酶即YME1L[15]和OMA1[16]还可在S1和S2位点进一步切割加工，产生可溶性的OPA1短型（short OPA1，S-OPA1）游离在IMM和线粒体外膜（outer mitochon-drial membrane，OMM）之间的线粒体膜间隙[17]。

1.2. OPA1参与线粒体动力学

L-OPA1对线粒体融合发挥着重要作用，而S-OPA1会促进线粒体分裂过程，在正常生理条件下，L-OPA1和S-OPA1两种形式的OPA1维持一定比例[18]。在应激条件（如线粒体膜电势降低或细胞凋亡等）下，L-OPA1被IMM肽酶快速彻底地剪切，使OPA1功能完全丧失，进而导致线粒体功能障碍，最后使得体内细胞死亡并出现组织退化[17]。

在细胞凋亡过程中线粒体的网状结构被破坏，线粒体嵴发生重构。有研究发现，OPA1还可与IMM和OMM之间的嵴连接处的线粒体超微结构直接相互作用，进而稳定线粒体膜曲率并维持嵴的完整性[19]。适当比例及一定数量的L-OPA1和S-OPA1的寡聚化，可使线粒体嵴连接保持紧密[20]；而当OPA1被抑制或者 OPA1发生致病突变时，会导致线粒体超微结构发生改变，嵴连接崩溃，最终导致线粒体断裂和细胞凋亡[21]。

1.3. OPA1参与线粒体能量学

越来越多证据表明，线粒体动力学与维持线粒体的能量密切相关，其中OPA1是连接线粒体形态和能量学的关键因素[22]。当细胞线粒体S-OPA1减少时，线粒体嵴减少，功能上也表现为氧化磷酸化缺陷，ATP水平下降[23]。

OPA1还与呼吸复合物的亚基直接相互作用，维持呼吸链的完整性并参与呼吸作用和能量代谢[24]。当OPA1减少时，可导致呼吸链复合物Ⅴ组装不完整，从而降低细胞耗氧率，ATP产生减少[22]。能量功能障碍还会导致线粒体摄取和保留Ca2+ 能力降低，进而使Ca2+ 稳态失衡并进一步恶化细胞表型[23]。

1.4. OPA1维持线粒体基因组稳定

线粒体DNA（mitochondrial DNA，mtDNA）具有独立的复制、转录和编码功能，可保证细胞能量代谢的相关活动和维持线粒体的结构和功能[25]。既往研究表明，mtDNA不稳定与OPA1表达减少导致的线粒体功能障碍相关[26]。这表明OPA1在维持mtDNA的稳定中发挥着重要作用。一些研究发现OPA1外显子4b结构域可直接与mtDNA作用，通过类核附着到IMM来促进mtDNA稳定[27]。当OPA1突变时，mtDNA会累积多个缺失突变，进而导致相关疾病发生[28]。在mtDNA突变的小鼠模型中，当线粒体融合过程遭受破坏时，会导致线粒体功能障碍和致死率显著增加，表明功能受损线粒体与正常线粒体融合后可稀释突变的mtDNA，从而保持mtDNA的稳定性，因此线粒体融合可能是mtDNA突变的保护因素[29]。

2. OPA1与骨骼系统疾病

2.1. OPA1与骨关节炎（osteoarthritis，OA）

OA是一种慢性退行性疾病，其发展过程主要为软骨细胞出现衰老和凋亡，导致软骨细胞外基质合成降解平衡失调，进而引起关节软骨退变、软骨下骨硬化、骨赘及软骨下囊肿形成，最终导致关节功能完全丧失[30]。据报道，OA患者的关节软骨细胞常出现衰老现象，该现象随着关节软骨组织退变的严重程度逐渐加剧[31]。Coryell等[32]指出，线粒体功能障碍可能是导致软骨细胞衰老的重要机制之一。研究发现，适度的机械应力可通过增强OPA1及MFN1、2的表达来促进线粒体融合，进而维持线粒体功能并减少软骨细胞凋亡[33]。

线粒体融合可产生新的线粒体，线粒体裂变可分离去极化和受损的线粒体，最后通过线粒体自噬将其消除，这样可有效减少活性氧（reactive oxygen species，ROS）的产生并抑制软骨细胞凋亡[34]。当线粒体动力学失调时会引起线粒体功能障碍，从而引起软骨细胞能量代谢障碍、ROS堆积、炎症因子释放，最后导致软骨细胞过度凋亡和软骨组织退化[35-37]。Ruiz-Romero等[38]利用蛋白组学方法发现，在人OA软骨细胞中，OPA1的表达明显低于正常软骨细胞。沉默信息调节因子3（sirtuin-3，SIRT3）可去乙酰化并激活OPA1，从而显著改善线粒体动力学[39-40]。近年研究表明，二氢杨梅素可激活SIRT3，调节软骨细胞中的线粒体动力学以维持线粒体稳态，从而发挥抗软骨组织退化作用[41]。FGF-18通过磷脂酰肌醇 3-激酶/蛋白激酶 B （phosphati-dylinositol 3-kinase/protein kinase B，PI3K/AKT）信号通路显著增加OPA1和MFN2的表达，恢复线粒体功能并减少软骨细胞凋亡[42]。这提示OPA1可能是治疗软骨退化和OA的潜在靶点。

2.2. OPA1与骨质疏松症

骨质疏松症是一种常见的全身性骨骼疾病，其特征是破骨细胞的骨吸收增加和成骨细胞的骨形成减少，导致净骨质流失和骨脆性增加，最后增加骨折风险[43-44]。当过多ROS产生时，会导致成骨细胞的线粒体功能障碍，从而引起细胞凋亡[45]。Jia等[46]的研究发现，当成骨细胞被镉诱导细胞凋亡时，线粒体会发生功能障碍，线粒体融合蛋白OPA1和MFN2的表达水平将会降低。Cai等[47]的研究表明，羟基酪醇可通过激活AKT-GSK3β信号通路减少OPA1切割，从而有效维持线粒体融合和分裂间的平衡，减少线粒体功能障碍和氧化应激诱导的成骨细胞凋亡。此外，ROS水平升高诱导的线粒体损伤可导致骨相关MSCs功能障碍，从而破坏其成骨细胞潜能[48]。Chen等[49]通过构建生物功能的金属有机骨架涂层，在植入物上表达超氧化物歧化酶和过氧化氢酶活性，分解MSCs中的ROS并恢复其线粒体功能，OPA1和MFN2等线粒体融合蛋白表达明显增加。这提示OPA1对预防或延迟骨质疏松症的骨量丢失具有重大意义。

2.3. OPA1与骨肉瘤

骨肉瘤是青少年常见的原发性骨肿瘤之一，也是青少年癌症死亡的主要原因[50]。骨肉瘤的复发风险非常高，因此发现新的治疗药物来降低复发风险并阻止其转移扩散至关重要。OPA1在抗骨肿瘤细胞中发挥着重要作用。Garcia等[51]的研究表明，在人骨肉瘤癌细胞系143B中，当ROS升高时会导致L-OPA1裂解，从而阻碍线粒体融合过程，导致线粒体网络的破碎。Huang等[52]的研究发现，鱼腥草可以抑制骨肉瘤过程，并显著降低线粒体融合相关蛋白OPA1和MFN1的表达，同时增加线粒体裂变相关蛋白FIS1的表达。Lai等[53]的研究表明，丹参酮ⅡA可以显著降低人骨肉瘤癌细胞系143B中MFN1、2和OPA1的表达，并增加裂变蛋白DRP1的表达，从而通过调节线粒体学来诱导癌细胞凋亡。Jones等[54]的研究表明，线粒体的跨膜电位损失会激活人骨肉瘤癌细胞系143B中OMA1对OPA1的切割和DRP1介导的裂变，从而破坏线粒体融合和裂变的平衡，导致线粒体网络破碎。这些研究结果表明，OPA1通过线粒体动力学维持生物能量的稳态，从而对骨肉瘤细胞活力产生影响。

2.4. OPA1与肌肉和其他骨骼系统疾病

OPA1介导的线粒体动力学也在肌肉系统疾病中扮演关键角色，例如肌肉减少症。研究发现线粒体功能障碍是导致肌肉减少症的关键因素[55]。肌肉减少症小鼠模型研究显示，身体机能和肌肉质量的下降和参与线粒体动力学的基因如OPA1和MFN2的表达水平降低相关[56]。Tezze等[57]的研究表明，OPA1缺失会导致内质网应激，从而引起一系列相关的信号级联反应，诱导全身衰老的分解代谢程序，最终导致机体肌肉萎缩和衰老死亡。此外，OPA1还可以通过线粒体动力学调节免疫微环境[58-59]，这可能为其他肌肉和骨骼系统疾病如类风湿性关节炎和强直性脊柱炎等，提供重要见解。

3. 线粒体动力学相关的生物活性成分及药物

骨骼系统疾病的发生机制目前尚未完全清楚，但越来越多证据表明，线粒体动力学在这一过程中起着重要作用。最新研究表明，通过调节线粒体功能来治疗骨骼系统疾病是一个新兴研究方向[2]。一些具有生物活性成分的药理分子和常规药物，通过靶向线粒体动力学，可以在一定程度上延缓骨骼系统疾病的进展（表1）。尽管如此，大多数生物活性物质和药物治疗骨骼系统疾病仍处于临床前阶段，未来需要进行大规模临床研究来验证其疗效和安全性。

表 1.

Mitochondrial dynamics-related bioactive ingredients and drug prevention and treatment of skeletal system diseases

线粒体动力学相关生物活性成分及药物防治骨骼系统疾病

骨骼系统疾病
Skeletal system
disease		 生物活性成分及药物
Bioactive ingredients
and drug		 作用机制
Mechanism		 参考文献
Reference
OA FGF-18 通过 PI3K-AKT 信号通路，显著增加 OPA1 和 MFN2 的表达，从而恢复线粒体功能并减少软骨细胞凋亡 [42]
二氢杨梅素 通过激活 SIRT3，使得线粒体动力学相关蛋白 MFN2、DRP1 及 FIS1 的表达水平显著增加，进而维持线粒体稳态并抑制软骨细胞凋亡 [41]
二甲双胍 通过改善线粒体动力学，即 MFN2 表达增加和 DRP1 表达降低，清除功能失调的线粒体，抑制氧化应激和炎症 [60]
鸢尾素 通过改善线粒体动力学，即 MFN1 表达增加和 DRP1 表达降低，抑制 OA 软骨细胞中线粒体功能障碍介导的氧化应激并上调软骨细胞外基质的上调 [61]
硫化氢 通过选择性抑制 PI3K/AKT 和丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路，使得软骨细胞中 DRP1 表达降低，进而拮抗线粒体功能障碍，减少软骨细胞凋亡 [62]
骨质疏松症 羟基酪醇 通过激活 AKT-GSK3β 信号通路，减少 OPA1 切割，维持线粒体融合和分裂之间平衡，从而减少线粒体功能障碍和氧化应激诱导的成骨细胞凋亡 [47]
水飞蓟素 通过抑制成骨细胞中 L-OPA1 被切割成 S-OPA1 及降低 FIS1 表达，使得线粒体动态平衡向有利于线粒体融合方向进行，抑制晚期糖基化终末产物诱导的成骨细胞凋亡 [63]
骨肉瘤 鱼腥草 通过破坏线粒体融合和裂变的平衡，使得 OPA1 和 MFN1 的表达显著降低，而 FIS1 表达增加，使线粒体网络破碎进而抑制骨肉瘤细胞 [52]
丹参酮ⅡA 通过破坏线粒体动力学平衡，使得 OPA1 和 MFN1、2 显著减少而 DRP1 增加，进而诱导骨肉瘤细胞凋亡 [53]
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4. 小结

OPA1是调节线粒体动力学的关键分子，它通过线粒体融合稀释线粒体氧化还原过程中产生的大量ROS，还能通过线粒体裂变及时清除细胞中的受损线粒体，并维持呼吸链的完整性和mtDNA的稳定性。最近研究表明，线粒体功能障碍是骨骼系统疾病发生、发展的重要原因之一，而OPA1则能显著改善线粒体动力学并维持线粒体形态及功能稳定。虽然有研究发现一些药物分子及生物活性成分可以改善线粒体动力学，从而延缓骨骼系统疾病进展，但对于涉及OPA1参与调控机制的研究仍较为缺乏。因此，未来应深入探索 OPA1介导的线粒体动力学在骨骼系统疾病中的作用，并为其作为骨骼系统疾病的治疗靶点提供理论基础。

利益冲突　在课题研究和文章撰写过程中不存在利益冲突；项目经费支持没有影响文章观点

作者贡献声明　沈彬：综述设计、构思及修改；孙凯博：撰写文章；吴元刚、曾羿、李明阳、武立民：收集资料和查阅文献，对文章结构、逻辑提供建议

Funding Statement

国家自然科学基金资助项目（81974347、82272561）；四川省科技厅重点研发项目（2022YFS0050、2023YFS0096）；中国博士后基金资助项目（2021M702351）；四川省卫生健康委员会医学科技项目（21PJ040）

National Natural Science Foundation of China (81974347, 82272561); Foundation of the Science & Technology Department of Sichuan Province (2022YFS0050, 2023YFS0096); Project Supported by the China Postdoctoral Funds (2021M702351); Medical Science and Technology Project of Sichuan Provincial Health Commission (21PJ040)

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