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标题：Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes
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作者：Irene Lopez-Fabuel ; Juliette Le Douce ; Angela Logan 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13063-13068
DOI：10.1073/pnas.1613701113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNeurons depend on oxidative phosphorylation for survival, whereas astrocytes do not. Mitochondrial respiratory chain (MRC) complexes can be organized in higher structures called supercomplexes, which dictate MRC electron flux and energy efficiency. Whether the specific metabolic shapes of neurons and astrocytes are determined by the specific organization of MRC complexes is unknown. Here, we found that, in astrocytes, most complex I is free, resulting in poor mitochondrial respiration but high reactive oxygen species (ROS) production. In contrast, neurons show complex I to be mostly embedded into supercomplexes, thus resulting in high mitochondrial respiration and low ROS production. Thus, MRC organization dictates different bioenergetics preferences of neurons and astrocytes impacting on ROS production, possibly playing a role in neurodegenerative diseases. Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.
关键词：redox ; brain ; bioenergetics ; lactate ; glycolysis