广州生物院揭示线粒体疾病中的线粒体功能互补之谜

　　

　　2月24日，国际学术期刊Cellular and Molecular Life Sciences 在线发表了中国科学院广州生物医药与健康研究院刘兴国研究组的最新研究成果 Mitochondrial fusion provides an "initial metabolic complementation" controlled by mtDNA。该研究揭示了线粒体疾病中的线粒体功能互补之谜，首次发现一种新的线粒体功能互补模式：“初始代谢补偿”效应及其调控机制。该发现对线粒体间物质交换和功能补偿效应带来了“概念性”的突破，为线粒体疾病的治疗提供了理论基础和新的靶点。

　　线粒体是真核生物的“能量工厂”，是细胞内能量货币ATP的主要产生场所，它们不断地进行融合和分裂，呈线状或粒状。线粒体含有独立的遗传物质线粒体DNA。线粒体DNA突变不仅与衰老及退行性疾病（如帕金森疾病，老年痴呆疾病）相关，还能引起150多种遗传疾病（如LHON视神经萎缩症，线粒体脑肌病，线粒体肝病）。与核基因突变不同，线粒体DNA突变往往是异质性的，会导致细胞内同时含有野生型线粒体DNA和突变型线粒体DNA。无论在哪种线粒体DNA突变引发的疾病中，都存在“阈值效应”：只有当线粒体DNA突变积累到一定比例时，细胞的线粒体呼吸功能才会受到影响，同时临床症状才会出现。“阈值效应”这一线粒体疾病的重要特征已发现多年，基于此，有人曾提出线粒体之间融合进行物质交换实现互补的假说，但其可能的模式与机制至今仍是谜一般的“黑匣子”。

　　刘兴国研究组建立了新的细胞模型，并应用新的成像学方法，发现当线粒体的DNA丧失功能时，它们之间的同源融合能力很低，但是与正常线粒体保持了很高的异源融合能力从而在短时间内获得代谢功能的补偿，称为“初始代谢补偿”。该研究揭示了线粒体疾病中“阈值效应”的线粒体功能互补之谜：首先是短时的“初始代谢补偿”，其次是长时的依赖于正常线粒体DNA表达的补偿。更重要的是，研究组以“初始代谢补偿”为线粒体疾病的新的治疗靶点，筛选到了新的候选基因药物及小分子药物。

　　该研究获得中科院、科技部、国家自然科学基金、广东省和广州市的经费支持。

 

线粒体疾病中的线粒体功能互补之谜

线粒体初始功能补偿

原文摘要：

Mitochondrial fusion provides an "initial metabolic complementation" controlled by mtDNA

Heteroplasmic cells, harboring both mutant and normal mitochondrial DNAs (mtDNAs), must accumulate mutations to a threshold level before respiratory activity is affected. This phenomenon has led to the hypothesis of mtDNA complementation by inter-mitochondrial content mixing. The precise mechanisms of heteroplasmic complementation are unknown, but it depends both on the mtDNA nucleoid dynamics among mitochondria as well as the mitochondrial dynamics as influenced by mtDNA. We tracked nucleoids among the mitochondria in real time to show that they are shared after complete fusion but not 'kiss-and-run'. Employing a cell hybrid model, we further show that mtDNA-less mitochondria, which have little ATP production and extensive Opa1 proteolytic cleavage, exhibit weak fusion activity among themselves, yet remain competent in fusing with healthy mitochondria in a mitofusin- and OPA1-dependent manner, resulting in restoration of metabolic function. Depletion of mtDNA by overexpression of the matrix-targeted nuclease UL12.5 resulted in heterogeneous mitochondrial membrane potential (ΔΨm) at the organelle level in mitofusin-null cells but not in wild type. In this system, overexpression of mitofusins or application of the fusion-promoting drug M1 could partially rescue the metabolic damage caused by UL12.5. Interestingly, mtDNA transcription/translation is not required for normal mitochondria to restore metabolic function to mtDNA-less mitochondria by fusion. Thus, interplay between mtDNA and fusion capacity governs a novel 'initial metabolic complementation'.