2023, Vol. 30
2. 复旦大学附属中山医院实验研究中心，上海 200032
2. Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China
线粒体是真核细胞生物中普遍存在的、双层膜结构的一种细胞器。线粒体在细胞内数量巨大，自身具有强大的运动能力，可移动至对能量要求高、代谢旺盛的组织和细胞，而在低耗能的组织中较少。线粒体作为机体内能量代谢的“发动机”，绝大部分的脂类、蛋白质、糖类在线粒体内进行有氧代谢，通过三羧酸循环转化成细胞能直接利用的ATP，为细胞提供超过90%的ATP；同时，线粒体作为一种半自主细胞器，拥有自身的遗传信息，不仅能为细胞供能，还直接参与细胞分化、信息传递和凋亡等过程[1]，调节细胞内Ca2+传递，调控细胞生长和疾病的能力[2]。然而，线粒体在代谢产能的同时会产生大量超氧化物，且易受到氧化应激的损害。因此，线粒体一直处于快速的代谢状态，而正常状态下线粒体主要通过自身动力学和自噬来维持健康和稳定。
1 线粒体动力学和自噬线粒体动力学分为融合和分裂2个过程，两者的平衡决定了线粒体的结构和功能。融合是一个不同线粒体之间进行物质交换和互补的过程[3]，轻度损伤的线粒体通过这个过程，利用其他健康线粒体的蛋白、DNA等进行自我修复。目前普遍认为增加线粒体融合过程可以对抗轻度损伤或应激环境[4]。融合过程主要依赖外膜的融合蛋白（mitofusin，Mfn）和内膜的视神经萎缩蛋白1（optic atrophy 1，OPA1）。Mfn分为Mfn1和Mfn2，两者结构高度相似，在融合过程中，Mfn2与Mfn1协同促使不同的线粒体相互靠近。当2个线粒体距离小于7 nm后，GTP水解酶将线粒体外膜融合；然后在内膜OPA1的作用下，内膜融合，完成2个线粒体的融合[5]。胞浆中的动力相关蛋白1（dynamin related/like protein 1, DRP1/DLP1）参与线粒体分裂，分裂蛋白DRP1聚集到线粒体外膜，形成环状结构并不断环缩，最终将1个线粒体一分为二[6]。分裂的结果可以是2个健康的线粒体，也可能是1个健康的线粒体和1个损伤的线粒体，甚至是线粒体的碎片。当细胞发生凋亡或线粒体膜电位下降时，线粒体分裂增加，将濒死的线粒体碎片化，然后通过自噬途径消除[7]，所以线粒体的分裂是维持线粒体结构和调整mtDNA分布的必须步骤[8]。目前认为，融合负责维持线粒体的生物合成和内部稳态，促进细胞存活[9]；分裂负责线粒体的分布、促进线粒体自噬和突触的生长[10]。两者处于“此消彼长”的平衡状态[11]，抑制DRP1可增加OPA1的表达[12]，两者相互协调以维持线粒体的质量和数量。
自噬是细胞吞噬自己和自身碎片的过程，即需要被降解的部分被双层膜包裹后与溶酶体融合形成自噬溶酶体，然后进行降解并且选择性回收、利用所包裹的内容物，以实现细胞的代谢需要和更新。线粒体自噬是清除损伤线粒体的主要途径。最常见的途径为Parkin /Pink1（PTEN-induced putative kinase 1），其他有Bnip3（Bcl-2/adenovirus E1B 19-kDa-interacting protein 3）、NIX（nip-like protein）和FUNDC1途径等。受到严重创伤的线粒体膜电位下降，促使原本通过线粒体外膜TOMM20通道进入线粒体内水解的Pink1在线粒体外膜积聚、召集Parkin，引起线粒体外膜蛋白的泛素化后与LC3Ⅱ结合，诱导自噬[13]。Bnip3和NIX同属于Bcl-2蛋白家族，在线粒体自噬过程中互相影响又相互独立。Bnip3通过抑制促凋亡蛋白Bcl-2、激活Bax；NIX则通过抑制Caspase3蛋白启动自噬[14]。在Bnip3被敲除时，NIX会代偿性增加[14]。FUNDC1则主要发生在内质网和线粒体连接区域，在低氧刺激下Serine 17位点被激活，然后结合LC3Ⅱ启动自噬过程[15]；FUNDC1减少，则Bnip3和NIX会代偿增强。线粒体自噬体与溶酶体结合后被降解[16-17]。线粒体自噬在正常的生理状态和异常的病理状态下均存在[18]，过度线粒体自噬会导致线粒体数量减少，引起线粒体功能异常和细胞死亡[19]。
然而，在一个完整的、拥有正常功能的机体中，线粒体动力学和线粒体自噬互相关联、相互作用。抑制自噬蛋白Pink1，细胞线粒体碎片增多；过表达自噬蛋白Parkin/Pink1则能抑制敲减DRP1所导致的线粒体延长[20]。同时，抑制线粒体分裂会导致自噬蛋白Parkin/Pink1减少[21]；过表达自噬蛋白Parkin/Pink1促使线粒体分裂[22]。融合蛋白Mfn2也参与影响Pink1-Mfn2-Parkin介导的线粒体自噬，泛素化的Mfn2参与Pink1-Mfn2-Parkin诱导的线粒体自噬，清除损伤的线粒体碎片；非泛素化的Mfn2参与线粒体的融合、促进细胞存活[23]。因此，健康的线粒体需要线粒体动力学和线粒体自噬维持于平衡状态[13]。线粒体的质量和数量在机体发生疾病过程中起着重要作用，本文主要从神经系统病变、代谢性疾病和心血管疾病[24]等方面简要概括目前线粒体扮演的角色和作用。
2 线粒体与神经系统疾病大脑虽然只占人体质量的2%，但其耗氧量占全身的25%，是全身最活跃、信号传递最频繁的器官。线粒体损伤与神经系统疾病密切相关[25-26]。线粒体动态结构在确保快速满足不同神经元能量需求以维持神经元和轴突能量稳态方面发挥着至关重要的作用[27]。线粒体运动和分布异常影响神经元的功能[28]。
在神经元发育早期，线粒体主要集中在活跃的生长锥细胞附近[29]，提供足够能量支持的同时，参与调控神经传递中重要的Ca2+传递。在这个过程中，敲除融合蛋白OPA1或者分裂蛋白DRP1会影响小鼠胚胎发育，导致其孕中期死亡[30]。敲除前脑神经元的DRP1的小鼠出生后表现为线粒体ATP生成异常、海马萎缩，记忆和学习能力下降[31]；在提取的胚胎海马神经元中，过度表达DRP1会导致线粒体碎片化增加，阻碍树突分枝的形成，线粒体网络结构异常；而敲减DRP1蛋白表达则产生相反的效果[32]。但在成年小鼠中适当过度表达DRP1可以促进成年小鼠的海马初始神经元成熟，增加突触的长度和连接，改善海马神经元的生成和记忆功能[33]。此外，海马神经元树突棘的发育过程也离不开活跃的线粒体活动，线粒体生物合成和形态异常可以导致树突棘生成、树突网络的异常连接[34]。
线粒体动力学异常对已经成熟的神经细胞也有影响。细胞在饥饿状态时，线粒体DRP1磷酸化减少，以维持细胞正常ATP的产生[4]。氧气/葡萄糖剥夺（oxygen/glucose deprivation，OGD）后，增加DRP1蛋白Ser656、Ser637位点磷酸化，神经细胞线粒体受损，ROS增加，神经兴奋性毒性增加[35]，导致树突及突触形成障碍[36]。急性OGD模型的海马切片中CA1区锥体神经元线粒体自噬减少，线粒体长度缩短；神经元细胞数量呈现时间依赖性减少[37]。研究也发现下调融合蛋白表达可以加剧线粒体异常[38]，OPA1可对线粒体进行重构，改善多巴胺能神经毒性刺激下神经母细胞瘤SH-SY5Y细胞complex1的生成[39]；OPA1功能缺乏的小鼠则表现为突触结构异常[40]，谷氨酸能神经传递减弱[41]；Mfn蛋白表达异常会导致线粒体的位置分布和移动功能障碍，影响损伤线粒体的清除[42]。在体及离体实验中，谷氨酸受体激动剂N-甲基-D-天冬氨酸(N-methyl-D-aspartic，NMDA，30 μmol/L）刺激皮层神经元，能下调Mfn2表达，影响细胞内Ca2+稳态，导致线粒体功能异常并产生神经兴奋性毒性；外源性的补充Mfn2可以对抗NMDA引起的细胞死亡[43]。受损的线粒体会导致线粒体碎片的积累，导致线粒体氧化应激水平升高[44]，进一步增加细胞死亡[45]。线粒体自噬增加可以加快损伤线粒体的清除[46]。所以，上调细胞内线粒体自噬Bnip3蛋白[47]、NIX蛋白[48]以及Parkin/Pink1蛋白[49]，增加线粒体自噬，可以减少细胞凋亡并保护神经元功能。
2.1 阿尔茨海默病（Alzheimer disease, AD）神经元极性丧失和轴突微管相关蛋白错位是AD的典型表现，通过活细胞照相技术发现线粒体在AD神经元轴突起始段内呈偏置分布，存在近端聚簇和相对缺失，且这部分线粒体活性降低，提示线粒体簇的适当功能对维持神经元极性至关重要[50]。同时，受损的线粒体积聚是神经退行性变的特征之一。AD患者海马区神经元的线粒体体积减小，损伤的线粒体增多，提示线粒体分裂增多和（或）融合减少[51]。通过对TOMM20与LAMP2共定位及电镜观察发现，线粒体自噬在AD患者的海马神经元和小胶质细胞中都有减少；在线虫和小鼠AD模型中发现，线粒体损伤后ATP产生异常，虽然有AMPK途径代偿性激活，最终不能逆转神经退行性变[52]。AD脑中Aβ沉积蛋白还可以与CDK5（cyclin dependent kinase 5）作用，增强DRP1的Ser579的磷酸化，激活caspase3（cysteine-aspartic acid protease 3）细胞凋亡通路；增强Ser585磷酸化能促进NMDA受体与谷氨酸结合，增强神经兴奋性毒性，加重AD患者认知记忆功能障碍[51]。通过抑制线粒体分裂Mdivi-1（mitochondrial division inhibitor 1）能减少脑内Aβ1-42、Aβ1-40蛋白；改善小胶质细胞功能，抑制中枢神经炎症；同时下调AD相关的Tau超磷酸化，改善AD患者的记忆和认知功能[52]。
2.2 帕金森病（Parkinson disease，PD）PD脑中α突触蛋白（α-Syn）与细胞内可溶性单体结合形成了不可溶的Lewy体，不可溶蛋白的沉积导致神经元死亡[53]。E3泛素化连接酶Parkin的点突变/缺陷是家族性PD中最常见的一种基因突变，其突变可导致海马神经元细胞表面NMDA和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的表达和兴奋性突触后电流变化，引起兴奋性谷氨酸能神经传递异常[54]。但是PD患者Pink1功能下调，线粒体碎片清除障碍，造成大量超氧化物在细胞内堆积；LRRK2（leucine-rich repeat kinase 2）是与PD关联最密切的单个基因，PD患者α-Syn的积聚导致LRRK2突变，LRRK2增加DRP1的Ser-616 (aka Ser-579)、Ser-637和Thr-595磷酸化，引起线粒体自噬异常，导致线粒体分裂和碎片化积聚[55]。而Pink1的过表达能减少神经元凋亡，改善PD患者的认知功能[56-57]。
3 线粒体与2型糖尿病随着生活质量逐步提高，代谢性疾病的发病率逐年上升，其中最具代表性的是以胰岛素抵抗导致胰岛素相对不足为主要特征的2型糖尿病。胰岛素的调控涉及很多方面，线粒体是其中的主要因素，线粒体异常及mtDNA突变是2型糖尿病发生发展的原因之一[58]。长期的高血糖状态下，线粒体异常产生ROS增多，诱发胰岛素抵抗，引起糖尿病并发症[59]。
高糖作为一个能量过剩的状态，会促使线粒体动力学倾向于线粒体分裂[60]，所以2型糖尿病患者的线粒体显著小于健康人[61]，线粒体碎片明显增多[62-63]。下调融合蛋白Mfn2表达可以加剧线粒体异常，并通过JNK途径增加肝脏的胰岛素抵抗[38]；而增加线粒体融合蛋白Mfn或OPA1表达，促进线粒体融合能改善肝脏的胰岛素抵抗[64-65]。在糖尿病患者心脏中，下调分裂蛋白DRP1表达、减少分裂、减少DRP1的Ser616的磷酸化都可以改善心肌的脂质代谢和胰岛素抵抗[66]。糖尿病小鼠分离出来的冠状内皮细胞中，DRP1表达增加，线粒体碎片化和氧化产物增加[67]；而抑制DRP1蛋白可以改善糖尿病内皮功能障碍导致的冠状动脉粥样硬化[68]。在糖尿病肾病中，线粒体相关内质网形成与肾功能正相关，与肾小管间质病变负相关；糖尿病小鼠的肾小管中线粒体破碎，伴随DRP1和BECN1的表达改变[69]。
高糖引起的血管病变是多种糖尿病并发症的病理基础，这是由于血管硬化可导致组织缺氧。用低氧和高糖处理小鼠的Neuro-2a细胞模拟糖尿病状态下的慢性脑低灌注发现，Bnip3介导的线粒体自噬缺陷，导致异常线粒体积聚，引起神经元死亡[70]。给予人神经上皮瘤细胞、人神经母细胞瘤细胞和海马神经元高糖刺激发现，25 mmol/L的高糖环境会导致ROS增加近2倍，cleaved caspase3和cleaved caspase9表达增加，细胞存活下降，沉默Pink1基因后细胞凋亡进一步增加[45]，提示线粒体自噬可能在高糖环境中通过抑制ROS积聚和细胞凋亡发挥保护神经系统的作用。而促进背根神经节线粒体转录因子A（mitochondrial transcription factor A，TFAM）的表达，能激活mtDNA的复制和转录，改善糖尿病的周围神经病变[71]。自噬激动剂雷帕霉素可改善糖尿病小鼠模型的肾小球硬化、系膜增生，减少蛋白尿[72]。
线粒体分裂抑制剂Mdivi-1、dynasore、肽抑制剂P110、15-oxospiramilactone（S3）促进线粒体融合，改善糖尿病的胰岛素抵抗，减缓脑部、肾脏等器官并发症的发生[73]。运动作为糖尿病治疗过程中一个重要的辅助环节，能调节Mfn2/DRP1比例、减少线粒体膜电位丢失和细胞色素酶C的释放[74]，有效保护db/db小鼠心肌。
4 线粒体与心血管疾病心脏是另一个对能量高需求的器官，每1次心肌的收缩舒张都需要大量ATP[3]。研究[75]发现，敲除融合蛋白Mfn1和Mfn2后，线粒体碎片化增加、线粒体自噬减少、心脏扩大；敲除分裂蛋白DRP1线粒体延长、线粒体数量减少，心肌坏死增加。Mfn和DRP1同时敲除的小鼠生存期长于单分子敲除的小鼠，提示线粒体的融合、分裂过程互相制约又相辅相成[76]。敲除融合基因OPA1会导致线粒体嵴异常、心脏射血分数下降，小鼠宫内死亡[77]。DRP1特敲后的心肌细胞的生物合成减少，电子呼吸链的传递活性下降，而心肌细胞特敲MyH6-Drp1 KO小鼠出生后普遍表现为心动过缓并在出生后2~3周死亡[78]。出生后小鼠经三苯氧胺敲除心脏DRP1基因后，心肌线粒体形态异常，最终在13周内因左心功能衰竭死亡[79]。
心脏缺血再灌注损伤可以下调分裂蛋白DRP1磷酸化水平，使线粒体体积增加、线粒体自噬减少，导致去极化线粒体大量堆积，心肌凋亡增加[80]。使用线粒体分裂蛋白的抑制剂Mdivi-1、dynasore、Pim-1可以抑制冠状动脉内皮细胞内线粒体破坏，减少细胞凋亡，改善内皮细胞功能[81]，最终缩小心肌梗死面积[82]。适当增加融合OPA1（基础水平1.5倍）可稳定线粒体嵴，对心肌具有保护作用[83]；Mfn2又分别从促进融合和Parkin/Pink1自噬参与应激状态下的心肌保护[84]。然而，Papanicolaou等[84]在心脏缺血再灌注损伤模型中的研究[84]发现，Mfn2敲除后由于Ca2+超载或ROS导致的线粒体通透性改变延迟，心肌细胞更容易存活。对心肌梗死再灌注的小鼠进行外源性线粒体移植可以增加Nrf2及其下游靶点的表达，减轻线粒体动力学失衡、改善线粒体自噬和线粒体功能，减轻心肌细胞损伤和凋亡[85-86]。而不同表达水平的FUNDC1及其在不同部位的磷酸化可以通过促进或抑制线粒体自噬来缓解或加重缺氧缺血再灌注损伤、心肌肥厚或代谢损伤。在心肌缺血阶段，线粒体自噬蛋白FUNDC1选择性地清除损伤线粒体，抑制心肌细胞凋亡；当缺血心肌恢复供血后，低氧环境解除促使FUNDC1调控自噬的能力下降，线粒体凋亡增加，导致缺血心肌损伤扩大[87]；同样敲除FUNDC1会导致心肌线粒体增大、功能下降，影响血小板功能和加剧心肌损伤[88]。此外，FUNDC1可以富集在线粒体和内质网之间的接触部位，调控线粒体相关膜的形成，调节细胞钙稳态和线粒体动力学，预防心功能障碍[89]。Bnip3也能增加缺血再灌注损伤心肌的线粒体自噬，提高细胞的存活率，改善预后[90]。Bnip3/NIX双敲除的小鼠心脏线粒体的形态和数量显著异常，促凋亡机制启动[91]。Pink1参与心肌的更新，敲除后的心肌细胞会发生病理性肥厚。终末期心力衰竭患者心脏Pink1表达减少，Pink1敲除的小鼠会进展为左心衰竭[91]。在主动脉缩窄的心衰小鼠模型中，线粒体自噬增加同样有利于清除损伤的线粒体、减少ROS，抑制心肌细胞凋亡[92]。
综上所述，线粒体动力学和线粒体自噬均在机体的正常运作中起重要作用。融合蛋白Mfn2同时影响线粒体融合过程和线粒体自噬过程，影响大于Mfn1；OPA1的作用主要在于调节线粒体嵴的形态和功能。线粒体的分裂和自噬则更像双刃剑。线粒体分裂蛋白DRP1广泛参与各个病理生理过程，在DRP1作用下线粒体的碎片化是线粒体自噬的起始步骤，其同时参与线粒体分裂和自噬过程。线粒体自噬是濒死的线粒体清除的主要途径，适度的分裂和自噬能使线粒体进行有效的更新换代，而一旦过度，则会导致线粒体数量减少，ATP产生异常改变，导致心、脑等能量高需求器官损害和能量代谢相关疾病发生。及时阻断线粒体损伤能有效缓解甚至治愈疾病；反之，线粒体损伤会进入失代偿，导致疾病进展，甚至导致死亡。目前认为线粒体与衰老具有密切相关性[93]，其参与退行性神经病变、糖尿病、心脏疾病等疾病的发生、发展和并发症发生的每一个阶段。因此，线粒体研究可以为常见的衰老或能量代谢相关疾病提供新的治疗靶点。
利益冲突： 所有作者均声明不存在利益冲突。
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