Roles for Mitochondrial Complex I Subunits in Regulating Synaptic Transmission and Growth.
Roles for Mitochondrial Complex I Subunits in Regulating Synaptic Transmission and Growth.
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DOI：
10.3389/fnins.2022.846425
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发表时间：
2022
影响因子：
4.3
通讯作者：
Frank, C. Andrew
中科院分区：
文献类型：
--
作者：
Mallik, Bhagaban;Frank, C. Andrew
关键词：
为了识别与人类疾病相关的突触功能的保守成分，我们进行了遗传筛选。我们使用果蝇的神经肌肉接头（NMJ）作为模型。我们对选定的靶点进行RNA干扰，并通过电生理学方法检测突触功能和可塑性。我们将筛选的重点放在已知与人类神经或肌肉功能保守的遗传因子上（筛选了300个果蝇品系）。从我们的筛选中，线粒体复合物I（MCI）亚基基因（ND-20 L）的敲低降低了NMJ神经传递的水平。由于表型的严重性，我们进一步研究MCI功能。在神经元和肌肉中同时敲低核心MCI亚基导致神经传递受损。我们将这种神经传递功能定位于肌肉。靶向MCI的药理学表型模仿受损的神经传递表型。最后，MCI亚基敲除或药理学抑制导致严重的细胞学缺陷，包括NMJ生长减少和NMJ形态改变。线粒体是细胞生物能量学所必需的，并通过氧化磷酸化产生ATP。五种多蛋白复合物实现了这一任务，MCI是最大的。人类中受损的线粒体复合物I亚基与诸如帕金森病、Leigh综合征和心肌病的疾病相关。总之，我们的数据提出了在突触功能和可塑性的背景下复杂I的分析。我们推测，在人类MCI功能障碍的背景下，类似的神经元和突触缺陷可能有助于发病机制。
To identify conserved components of synapse function that are also associated with human diseases, we conducted a genetic screen. We used the Drosophila melanogaster neuromuscular junction (NMJ) as a model. We employed RNA interference (RNAi) on selected targets and assayed synapse function and plasticity by electrophysiology. We focused our screen on genetic factors known to be conserved from human neurological or muscle functions (300 Drosophila lines screened). From our screen, knockdown of a Mitochondrial Complex I (MCI) subunit gene (ND-20L) lowered levels of NMJ neurotransmission. Due to the severity of the phenotype, we studied MCI function further. Knockdown of core MCI subunits concurrently in neurons and muscle led to impaired neurotransmission. We localized this neurotransmission function to the muscle. Pharmacology targeting MCI phenocopied the impaired neurotransmission phenotype. Finally, MCI subunit knockdowns or pharmacological inhibition led to profound cytological defects, including reduced NMJ growth and altered NMJ morphology. Mitochondria are essential for cellular bioenergetics and produce ATP through oxidative phosphorylation. Five multi-protein complexes achieve this task, and MCI is the largest. Impaired Mitochondrial Complex I subunits in humans are associated with disorders such as Parkinson’s disease, Leigh syndrome, and cardiomyopathy. Together, our data present an analysis of Complex I in the context of synapse function and plasticity. We speculate that in the context of human MCI dysfunction, similar neuronal and synaptic defects could contribute to pathogenesis.
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影响因子：
4.3
作者：
Foriel S;Beyrath J;Eidhof I;Rodenburg RJ;Schenck A;Smeitink JAM
通讯作者：
Smeitink JAM
影响因子：
29
作者：
Guerrero-Castillo, Sergio;Baertling, Fabian;Nijtmans, Leo
通讯作者：
Nijtmans, Leo
影响因子：
4.3
作者：
Fato, Romana;Bergamini, Christian;Bortolus, Marco;Maniero, Anna Lisa;Leoni, Serena;Ohnishi, Tomoko;Lenaz, Giorgio
通讯作者：
Lenaz, Giorgio
影响因子：
8.8
作者：
Garcia CJ;Khajeh J;Coulanges E;Chen EI;Owusu-Ansah E
通讯作者：
Owusu-Ansah E
DOI：
10.1126/science.1179685
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Dickman DK;Davis GW
通讯作者：
Davis GW