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细胞间线粒体转运的研究进展

  • 文宇桥1,2

    机 构：

    1. 四川理工学院自动化与信息学院，614000

    2. 生物流变学与技术教育部重点实验室（重庆大学），400045

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  • 李晨3

    机 构：长治医学院基础医学部生理学教研室046000

    ×
  • 宋关兵2

    机 构：生物流变学与技术教育部重点实验室（重庆大学），400045

    角 色：通讯作者

    邮 箱：song@cqu.edu.cn

    作者简介：宋关兵. E-mail: song@cqu.edu.cn

    ×
  • 赵虎成2,4

    机 构：

    2. 生物流变学与技术教育部重点实验室（重庆大学），400045

    4. 清华大学航天航空学院，100084

    角 色：通讯作者

    邮 箱：zhaohc@mail.tsinghua.edu.cn

    作者简介：赵虎成. E-mail: zhaohc@mail.tsinghua.edu.cn

    ×
1. 四川理工学院自动化与信息学院，614000； 2. 生物流变学与技术教育部重点实验室（重庆大学），400045； 3. 长治医学院基础医学部生理学教研室046000； 4. 清华大学航天航空学院，100084

中图分类号: Q71 DOI

DOI:10.16476/j.pibb.2018.0089

Research Progress on Mitochondrial Transfer between Cells

  • WEN Yu-Qiao1,2

    Affiliation：

    1. School of Automation and Information Engineering, Sichuan University of Science and Engineering, Leshan 614000,China

    2. Key Laboratory of Biorheological Science and Technology Chongqing University, Ministry of Education, Chongqing 400045,China

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  • LI Chen3

    Affiliation：Department of Physiology, Changzhi Medical College, Changzhi 046000, China

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  • SONG Guan-Bing2

    Affiliation：Key Laboratory of Biorheological Science and Technology Chongqing University, Ministry of Education, Chongqing 400045,China

    Role：Corresponding author

    Email：song@cqu.edu.cn

    Biography：SONG Guan-Bing. E-mail: song@cqu.edu.cn

    ×
  • ZHAO Hu-Cheng2,4

    Affiliation：

    2. Key Laboratory of Biorheological Science and Technology Chongqing University, Ministry of Education, Chongqing 400045,China

    4. Institute of Biomechanics and Medical Engineering, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China

    Role：Corresponding author

    Email：zhaohc@mail.tsinghua.edu.cn

    Biography：ZHAO Hu-Cheng. E-mail: zhaohc@mail.tsinghua.edu.cn

    ×
1. School of Automation and Information Engineering, Sichuan University of Science and Engineering, Leshan 614000,China； 2. Key Laboratory of Biorheological Science and Technology Chongqing University, Ministry of Education, Chongqing 400045,China； 3. Department of Physiology, Changzhi Medical College, Changzhi 046000, China； 4. Institute of Biomechanics and Medical Engineering, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China

CLC: Q71 DOI

DOI:10.16476/j.pibb.2018.0089

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目录 contents

    摘要

    线粒体是真核生物能量代谢的重要细胞器,是细胞进行氧化磷酸化生成ATP的主要场所.他参与完成细胞能量代谢、维持离子浓度梯度、传递细胞凋亡信号等生理功能. 阿尔茨海默病、帕金森病、心肌梗塞等疾病与线粒体功能异常相关.近年来发现，由创伤或炎症造成脑、心脏、肺缺氧时在细胞间会发生线粒体转移.线粒体转移，作为一种进化上保守的现象可能与神经降解、心血管疾病等相关.

    Abstract

    Mitochondria are important organelles for eukaryotic energy metabolism and are the main sites for oxidative phosphorylation of cells to produce ATP. It participates in the physiological functions of cell energy metabolism, maintaining ion concentration gradient, and transmitting apoptosis signals. Diseases such as Alzheimer's disease, Parkinson's disease, and myocardial infarction are associated with mitochondrial dysfunction. In recent years, it has been found that mitochondrial transfer occurs between cells in the brain, heart, and lung during hypoxia caused by trauma or inflammation. Intercellular mitochondrial transfer, as an evolutionarily conserved phenomenon, may be associated with neurodegradation, cardiovascular disease, and the like.

    线粒体是真核细胞内的一种将有机物储存能量转换为ATP的细胞器,为细胞能量代谢的场所. 细胞代谢所需90%的ATP由线粒体产生,线粒体被称为细胞的“能量工厂”. 此外,线粒体还参与细胞中活性氧(reactive oxygen species,ROS)的生成、细胞氧化还原电位维持和信号转导、胞内离子的跨膜转运、基因表达及细胞调亡等[1]. 自20世纪50年代成功分离线粒体后，对线粒体的研究经历了重要的发展阶段. 由于线粒体在细胞凋亡等多种病理生理过程中扮演着重要的角色，线粒体与疾病关系近年来再次成为研究热点[2].

  • 1 线粒体结构与起源

    1

    线粒体由双层膜包被基质构成，外膜平整光滑，内膜向内折叠形成嵴. 线粒体内外膜之间有间隙，中央是基质. 基质内含有三羧酸循环所需的全部酶类，内膜上具有呼吸链酶系及ATP酶复合体.线粒体为生命维持和活动提供能量，是细胞内氧化磷酸化和形成ATP的主要场所[1]. 线粒体有自身的DNA，但基因组基因数量有限，线粒体只是一种半自主性细胞器. 线粒体一般呈粒状或杆状，在特异的生理状态下可呈环形、哑铃形、线状、分叉状或其他形状[1]. 线粒体精巧的结构使其具有能执行能量代谢、维持离子稳态、传递细胞凋亡信号等重要的生理功能.

    内共生起源学说(endosymbiosistheory)认为:一种含有三羧酸循环所需酶系和电子传递链的革兰氏阴性需氧菌（原线粒体）被真核生物细胞吞噬后,形成了共生关系. 真核生物利用原线粒体获得能量,原线粒体从真核细胞获得更适宜的生存条件,这种共生增加了细胞的生存能力,使其可适应更复杂的环境[3]. 经过长期的共生关系,原线粒体演变成了线粒体,将真核细胞中的糖酵解和原线粒体中的三羧酸循环和氧化磷酸化成功耦合[4]. 线粒体具有一定的自主性,能够独立编码、合成蛋白质. 线粒体与细菌具有遗传背景的相似性,如:a.线粒体DNA为环状,无内含子,与细菌DNA一致;b.线粒体核糖体与细菌70S核糖体在大小和结构上相似;c.线粒体中表达的蛋白质由线粒体DNA编码.

  • 2 线粒体与疾病

    2

  • 2.1 阿尔茨海默病

    2.1

    阿尔茨海默病(Alzheimer’s disease, AD)是一种神经系统退行性疾病,其主要临床表现为认知障碍、记忆力衰退、言语失调等, 且常常伴随有运动和精神失常[5]. AD患者与正常人群相比，线粒体许多酶的功能显著降低. 其中，由细胞核编码的脱氢酶与由线粒体DNA编码的呼吸链复合物酶活性降低最为明显[6]. 活性氧（reactive oxygen species，ROS）累积导致的氧化应激和能量代谢损伤是AD的明显特征. β-淀粉样蛋白（amyloid-βprotein，Aβ），是Aβ前体经由β-和γ-分泌酶连续剪切后形成的长度在 39～43个氨基酸的短肽，可以穿越血脑屏障. Aβ与线粒体相互作用而引起线粒体损伤被认为是AD发病的可能机制[7]. 在AD模型小鼠中，发现线粒体DNA缺失，钙离子平衡被打破. 线粒体大量地摄取钙离子引发神经元启动凋亡信号. 因此，调控线粒体中钙离子的浓度成为治疗AD的策略[8]. Aβ是AD患者神经元斑块的主要成分，主要来源于内质网、高尔基体、溶酶体等细胞器[9]. 在转基因小鼠模型中发现线粒体是β-淀粉样肽单体和寡聚体聚集的靶点，聚集具有时间依赖性[9]. Aβ寡聚体能提高线粒体内的ROS水平，导致氧化应激损伤线粒体引发其膜电势降低，这反过来又提高了ROS水平[10]. 在神经元中，线粒体在细胞核周围合成后借助微管和肌动蛋白来运输，使其分布于细胞之内. 研究发现Aβ可引起微管失去正常结构来影响线粒体在胞内的转运[11]. 也有报道认为β-淀粉样肽可以打开线粒体的渗透转换孔，使其功能异常而诱发AD产生[12].

  • 2.2 帕金森病

    2.2

    帕金森病（Parkinson disease，PD）作为一种老年神经系统退行性疾病，他是大脑黑质多巴胺神经元退变和纹状体多巴胺递质降低导致的[13].研究发现，PD患者的大脑黑质线粒体呼吸链酶复合物活性降低了30%～40%[14,15].编码呼吸链复合物DNA的突变与PD密切相关. PD患者淋巴细胞中呼吸链上的酶复合物活性也显著降低[16]. 动物实验发现，呼吸链上的酶复合物被抑制或者诱导细胞凋亡的药物（N-methyl-4-phenylpyridinium）被大脑黑质多巴胺神经元摄取后灵长类动物表现出PD症状[16]. 可见，线粒体功能异常与PD密切相关.

  • 2.3 心肌梗塞

    2.3

    心肌细胞线粒体除了生成ATP提供能量外，还直接参与调节肌浆钙离子平衡、控制内源性凋亡以及核基因表达[17].在心肌梗塞状态下，线粒体融合与分裂动力学易失衡，形成较多功能异常线粒体，这类线粒体产生的ROS是正常线粒体数倍，过量ROS损伤线粒体蛋白和DNA，并形成恶性循环[18].心肌细胞线粒体自噬是清除受损个体、降低其危害的一种保护机制. 正常生理状态下，线粒体自噬保持在一定水平，及时消除功能缺陷线粒体，为线粒体生物合成提供原料[18]. 目前心肌梗塞模型中研究比较一致的观点认为，无论是急性还是慢性心肌梗塞都能提高心肌细胞线粒体自噬水平，线粒体自噬增强有利于减少细胞死亡，抑制心梗的发生发展[19].

  • 3 线粒体在培养细胞间的穿梭

    3

    在Gerdes研究小组[20]发现微囊和细胞器可通过培养的PC12细胞间纳米尺度的小管连接（tunneling nanotubes,TNT）后，其他实验室也发现了细胞间存在功能线粒体和mDNA经过TNT的主动穿梭[21]. 最近十年进一步发现在哺乳动物，包括培养的人源细胞间存在线粒体穿梭.Spees等[21]应用长时间低浓度EB（ethidium bromide）处理来耗尽线粒体DNA的办法，建立了线粒体功能缺失的A549细胞系. 这种细胞系只能在含有丙酮酸盐和尿苷的培养基中才可以进行糖酵解. 当线粒体功能缺失的A549细胞与间充质干细胞（mesenchymal stem cell，MSC）或成纤维细胞共培养时，后者可为其提供线粒体. 获得线粒体后的细胞与正常的A549细胞相同，在常规培养基中可以进行有氧呼吸、生长、增殖[21]. 通过脂多糖诱导使肺泡上皮细胞急性损伤，骨髓来源的基质细胞线粒体会转移到上皮细胞内，这种转移被Miro1（a mitochondrial Rho-GTPase）调控[22]. 气道损伤模型小鼠或过敏性炎症小鼠的肺上皮细胞可以从MSC获得线粒体来降低活性氧的产生，供体细胞过表达Miro1，可增强细胞间线粒体转移[22,23]. 在受损的部位注入正常细胞作为线粒体来源，可以提高受损组织细胞的生存能力，突变connexin-43阻止线粒体转移后这种保护功能消失[23]. 机械损伤造成大脑局部缺血后，星型胶质细胞的线粒体会转移到神经元进行能量补偿[24]，但未见受伤后神经元线粒体转移到胶质细胞的报道. 可见，细胞可以借助外源正常的线粒体去保证能量供给和生物合成的需要. 在电子显微镜下观察到受损伤的线粒体在视网膜神经元轴突包被成微囊后转移到邻近胶质细胞中，被溶酶体降解. 其中，从视神经乳头的线粒体转移占的比例要远大于胞体[25]. 另外Osswald等[26]发现在胶质瘤中，细胞间形成一种有别于TNT的微管连接网，细胞核、钙离子、线粒体可穿梭. Li等[27]发现，抗氧化剂处理MSC可促进细胞间TNT的形成从而有利于线粒体转移. 最新研究还发现，在急性呼吸窘迫综合征小鼠肺中注射MSC后，可与巨噬细胞形成TNT连接，促进MSC线粒体向巨噬细胞转移，进而增强其吞噬病原菌的能力[28]. 尽管以上报道指出，线粒体转移对细胞的生存有益，但某些转移可能会对受体细胞有毒害作用. 例如，当MSC与肺微血管内皮细胞按1∶1的比例共培养时，MSC可诱导内皮细胞凋亡，在此过程中观察到由MSC向内皮细胞线粒体转移而引发ROS产生[29].

    将人白血病细胞移植到鼠体内，化疗后发现有来源于鼠细胞的线粒体替代人白血病细胞中被化疗损伤的线粒体，增强白血病细胞的生存能力，从而降低化疗效果[30]. 通过化疗或射线作用肿瘤细胞，使其线粒体DNA损伤，发现肿瘤细胞可以从其他正常细胞获得线粒体DNA而存活[30]. 还有的研究发现，药物治疗可使白血病细胞受损的线粒体通过TNT转移到MSC中，从而降低活性氧的产生，进而产生药物抵抗[31]. 可见，在肿瘤治疗策略中需要考虑线粒体转移. 目前文献只报道，肿瘤细胞可以利用其他正常细胞的线粒体来补救自身功能异常的线粒体. 也有人推测，细胞可以接受功能异常细胞的线粒体，如AD、PD可能是由于神经元接受功能异常的线粒体而导致[1]. 线粒体DNA突变使线粒体功能失常是许多疾病的发病原因.

  • 4 线粒体转移后引起细胞重新编程

    4

    线粒体转移可引起细胞重新编程. Plotnikov等[33]发现将肾小管细胞或心肌细胞与MSC共培养，MSC会向这些分化细胞转移线粒体，与此同时MSC表达有分化细胞特征的蛋白质 (Tamm-Horfsall protein and heavy chain myosin, respectively) [32,33]. 现在尚不清楚阻断线粒体转移可否抑制MSC的这种程序. Acquistapace等[34]证实，完全分化的心肌细胞与脂肪或间充质干细胞共培养，其最后状态类似于心肌祖细胞. 这个过程中涉及到脂肪或间充质来源干细胞向心肌细胞转移线粒体. 干细胞线粒体被EB破坏后，心肌细胞不再向祖细胞方向转化. Vallabhaneni等[35]报道MSC与血管平滑肌细胞共培养可增加其增殖速度，并伴随有平滑肌细胞线粒体向MSC转移. 破坏纳米管阻止线粒体转移，MSC不再增加其分裂速度.

  • 5 胁迫状态促进干细胞的线粒体转移

    5

    研究显示细胞生存环境是决定细胞器转移的主要因素. 人脐静脉内皮细胞（HUVESs）与鼠的内皮祖细胞（EPCs）在正常培养条件下，17% HUVECs接受到EPSs的线粒体转移. 当培养基中加入毒性物质阿霉素（adriamycin），这种转移会加倍，而且仅从EPC单向转移到HUVEC[36]. Wang 等[37]报道只有在血清饥饿或者暴露在硫化氢状态下海马神经胶质细胞才与神经元形成纳米管连接，并进行线粒体转移. Bhattacharya实验室[23]也报道，细胞损伤是线粒体转移的必须条件. 将MSC灌注到小鼠气管，线粒体可以转移到受损伤的肺表皮细胞，但不能转移到未受损伤的细胞. MSC不能将线粒体转移到健康的肺表皮细胞，可能是因为缺少损伤信号的原因. 因此，确定促进MSC线粒体转移的信号对干细胞治疗具有重要的临床意义. 总之，在正常状态下，可以发生细胞间线粒体转移. 但干细胞作为供体，需要在受体细胞损伤状态下才能转移. 哺乳动物细胞在不利生存状态时更容易接受细胞器，而不是捐献细胞器，可能是一种适应. 这与单细胞生物不同，如：具有纤毛的原生动物在温度胁迫或表面抗体侵袭时不会发生线粒体倾吐[38].

  • 6 线粒体转移的机制

    6

    线粒体转移详细的机制目前仍不清楚，纳米管道、细胞分泌囊泡、细胞间直接接触都可能是线粒体细胞间转移的途径(图1).

    图1 细胞间线粒体转移机制： 纳米管道（TNTs）、细胞分泌囊泡(endocytosis of vesicles)、细胞间直接接触(fusion)

    图1 细胞间线粒体转移机制： 纳米管道（TNTs）、细胞分泌囊泡(endocytosis of vesicles)、细胞间直接接触(fusion)

    Fig.1 Mechanism of intercellular mitochondrial transfer through tunneling nanotubes(TNTs), endocytosis of vesicles and cytoplasmic fusion

  • 6.1 纳米管隧道

    6.1

    最近，在动物细胞中发现了一种与植物胞间连丝类似的管状结构——隧道纳米管（TNT），这种哺乳动物细胞间的膜通道由肌动蛋白支撑，长度变异较大（50～70 nm），可以传输运载体、钙离子、线粒体、内质网等［20,21］. 2004年首次报道TNTs后,有研究者发现MSC可以通过TNT向其他细胞转移细胞器. 许多体外和动物受伤模型中证实，MSC有通过线粒体转移来实现其对受损细胞的保护和补救功能[23,39]. TNT结构的形成与细胞的生理状态相关，TNTs的形成有利于体内细胞间线粒体的转移.

  • 6.2 细胞外囊泡

    6.2

    细胞外囊泡(extracellular vesicle, EV)是由细胞释放到细胞外微环境的膜性囊泡，携带母细胞来源物质，参与机体的生理和病理活动过程. 根据来源的不同，细胞外囊泡可分为3类:外泌体、微泡、凋亡小体[40]. 其中，微泡体积最大，直径大约1 µm. 许多关于细胞间线粒体转移的研究报道指出，线粒体DNA和完整的线粒体可被包裹到微泡中，然后分泌被受体细胞接受. Spees等[21]首次应用荧光标记的办法观察到人间充质干细胞分泌含有线粒体的微泡到培养液中，然后被受体细胞吞噬.Islam等[23]报道由来源于骨的MSC微泡通过connexin-43将线粒体转移到表皮细胞.

  • 6.3 部分或完全细胞融合（partial or complete cell fusion）

    6.3

    有研究指出，细胞可能会通过部分或完全融合来获得外源线粒体. 来源骨髓的细胞一般会自发的与心肌细胞、肝细胞、浦肯野神经元进行自发性融合[41]. 通过细胞骨架介导的部分融合也可能是细胞从周围细胞获得线粒体的途径. 例如，恶性胶质瘤通过由connexin-43间隙连接形成的微管网进行细胞间线粒体传输，即通过细胞融合的方式来实现[42]. 但Spees等[21]证实细胞可以获得外源线粒体而不能获得外源细胞核，排除了完全融合的可能. 细胞是否可以通过完全融合的机制进行线粒体转移，仍需进一步研究.

  • 7 结束语

    7

    在近几十年的疾病研究发现，多种疾病与线粒体功能障碍有关，如癌症、肝病、卒中、帕金森病、老年痴呆等. 目前，以线粒体为靶点的药物分子设计及其机制研究已成为热门研究领域之一.细胞线粒体功能失常由正常细胞的线粒体来取代，是最近几年发现的现象. 这无疑为线粒体相关疾病的治疗提供了新的思路和策略.

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  • 基本信息

    DOI:10.16476/j.pibb.2018.0089

    中图分类号: Q71 DOI

    引用信息

    文宇桥,李晨,宋关兵等.细胞间线粒体转运的研究进展[J].材料研究学报,2018,XX(XX):1-7.

    WEN Yu-Qiao,LI Chen,SONG Guan-Bing,et al.Research Progress on Mitochondrial Transfer between Cells[J].Chinese Journal of Materials Research,2018,XX(XX):1-7.

    稿件历史

    纸刊出版 : 2018
    收稿日期 : 2018-05-01
    录用日期 : 2018-10-17

    • 文宇桥

    机 构：

    1. 四川理工学院自动化与信息学院，614000

    2. 生物流变学与技术教育部重点实验室（重庆大学），400045

    Affiliation：

    1. School of Automation and Information Engineering, Sichuan University of Science and Engineering, Leshan 614000,China

    2. Key Laboratory of Biorheological Science and Technology Chongqing University, Ministry of Education, Chongqing 400045,China

    李晨

    机 构：长治医学院基础医学部生理学教研室046000

    Affiliation：Department of Physiology, Changzhi Medical College, Changzhi 046000, China

    宋关兵

    机 构：生物流变学与技术教育部重点实验室（重庆大学），400045

    Affiliation：Key Laboratory of Biorheological Science and Technology Chongqing University, Ministry of Education, Chongqing 400045,China

    角 色：通讯作者

    Role：Corresponding author

    邮 箱：song@cqu.edu.cn

    作者简介：宋关兵. E-mail: song@cqu.edu.cn

    Biography：SONG Guan-Bing. E-mail: song@cqu.edu.cn

    赵虎成

    机 构：

    2. 生物流变学与技术教育部重点实验室（重庆大学），400045

    4. 清华大学航天航空学院，100084

    Affiliation：

    2. Key Laboratory of Biorheological Science and Technology Chongqing University, Ministry of Education, Chongqing 400045,China

    4. Institute of Biomechanics and Medical Engineering, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China

    角 色：通讯作者

    Role：Corresponding author

    邮 箱：zhaohc@mail.tsinghua.edu.cn

    作者简介：赵虎成. E-mail: zhaohc@mail.tsinghua.edu.cn

    Biography：ZHAO Hu-Cheng. E-mail: zhaohc@mail.tsinghua.edu.cn
    html/pibbcn/20180089/alternativeImage/141ab814-2dab-427e-8369-eb6be2d340b6-F001.jpg

    图1 细胞间线粒体转移机制： 纳米管道（TNTs）、细胞分泌囊泡(endocytosis of vesicles)、细胞间直接接触(fusion)

    Fig.1 Mechanism of intercellular mitochondrial transfer through tunneling nanotubes(TNTs), endocytosis of vesicles and cytoplasmic fusion

    image /

    无注解

  • 参 考 文 献

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    • 4

      Zaremba-Niedzwiedzka K, Caceres E F, Saw J H, et al. Asgard archaea illuminate the origin of eukaryotic cellular complexity. Nature, 2017, 541（7637）:353-358

    • 5

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