Mitochondrial fusion provides an ‘initial metabolic complementation’ controlled by mtDNA
Mitochondrial fusion provides an ‘initial metabolic complementation’ controlled by mtDNA
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线粒体融合提供了由 mtDNA 控制的“初始代谢互补”
DOI：
10.1007/s00018-015-1863-9
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发表时间：
2015-02
影响因子：
8
通讯作者：
Liu X
中科院分区：
文献类型：
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作者：
Bao F;Qin D;Pei D;Liu X
异质细胞，窝藏突变和正常的线粒体DNA（mtDNA），必须积累突变到阈值水平之前，呼吸活动受到影响。这一现象导致了线粒体DNA互补的假设，通过线粒体间的内容物混合。异质互补的确切机制尚不清楚，但它既取决于线粒体之间的mtDNA类核动力学，也取决于受mtDNA影响的线粒体动力学。我们在真实的时间内追踪了线粒体中的类核，以表明它们在完全融合后是共享的，而不是“吻了就跑”。采用细胞杂交模型，我们进一步表明，线粒体DNA少线粒体，其中几乎没有ATP的生产和广泛的Opa 1蛋白水解裂解，表现出弱的融合活性，但仍然有能力与健康的线粒体融合在一个mitofusin和OPA 1依赖的方式，导致恢复代谢功能。通过过度表达基质靶向核酸酶UL12.5而导致线粒体DNA的耗竭，在线粒体融合素缺失的细胞中导致细胞器水平上的不均匀线粒体膜电位（Δ Δ Δ m），但在野生型中则没有。在该系统中，过表达丝裂融合素或应用融合促进药物M1可以部分挽救由UL12.5引起的代谢损伤。有趣的是，正常线粒体不需要mtDNA转录/翻译来通过融合恢复无mtDNA线粒体的代谢功能。因此，线粒体DNA和融合能力之间的相互作用控制着一种新的“初始代谢互补”。
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'.
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影响因子：
5.3
作者：
Delettre, C;Griffoin, JM;Hamel, CP
通讯作者：
Hamel, CP
影响因子：
168.9
作者：
Schapira, Anthony H. V.
通讯作者：
Schapira, Anthony H. V.
影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
影响因子：
46.9
作者：
Chudakov, DM;Belousov, VV;Lukyanov, KA
通讯作者：
Lukyanov, KA
影响因子：
12.4
作者：
通讯作者：
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