Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors.
Human Dopaminergic Neurons Lacking PINK1 Exhibit Disrupted Dopamine Metabolism Related to Vitamin B6 Co-Factors.
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DOI：
10.1016/j.isci.2020.101797
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发表时间：
2020-12-18
期刊：
影响因子：
5.8
通讯作者：
Fitzgerald JC
中科院分区：
文献类型：
--
作者：
Bus C;Zizmare L;Feldkaemper M;Geisler S;Zarani M;Schaedler A;Klose F;Admard J;Mageean CJ;Arena G;Fallier-Becker P;Ugun-Klusek A;Maruszczak KK;Kapolou K;Schmid B;Rapaport D;Ueffing M;Casadei N;Krüger R;Gasser T;Vogt Weisenhorn DM;Kahle PJ;Trautwein C;Gloeckner CJ;Fitzgerald JC
PINK 1功能缺失突变导致早发性帕金森病PINK 1-帕金介导的线粒体自噬已经得到了很好的研究，但大脑中内源性过程的相关性仍有争议。在这里，人类多巴胺能神经元中PINK 1的缺乏抑制了离子载体诱导的线粒体自噬并降低了线粒体膜电位。补偿性线粒体更新维持线粒体形态并保护呼吸链。这是由代谢变化引起的，包括TCA循环酶肌醇三磷酸酶的抑制、NAD+的积累和代谢物消耗。PINK 1的丢失通过严重影响其合成和摄取来破坏多巴胺代谢。该机制涉及将关键氨基酸转向能量产生而不是神经递质代谢，并涉及使用无偏多组学方法鉴定的与维生素B6补救途径相关的辅因子。我们认为，PINK 1信号不能控制的线粒体膜电位的降低启动了代谢补偿，这与帕金森病相关的神经代谢后果。PINK 1 KO hDAN不经历离子载体诱导的线粒体自噬，但CI保持活性PINK 1 KO通过肌醇三磷酸酶影响TCA循环，导致关键氨基酸的耗尽PINK 1 KO沉默PNPO，其提供必需的生物辅因子PINK 1功能丧失减少多巴胺库和神经递质摄取分子生物学;分子神经科学;干细胞研究;组学
PINK1 loss-of-function mutations cause early onset Parkinson disease. PINK1-Parkin mediated mitophagy has been well studied, but the relevance of the endogenous process in the brain is debated. Here, the absence of PINK1 in human dopaminergic neurons inhibits ionophore-induced mitophagy and reduces mitochondrial membrane potential. Compensatory, mitochondrial renewal maintains mitochondrial morphology and protects the respiratory chain. This is paralleled by metabolic changes, including inhibition of the TCA cycle enzyme mAconitase, accumulation of NAD+, and metabolite depletion. Loss of PINK1 disrupts dopamine metabolism by critically affecting its synthesis and uptake. The mechanism involves steering of key amino acids toward energy production rather than neurotransmitter metabolism and involves cofactors related to the vitamin B6 salvage pathway identified using unbiased multi-omics approaches. We propose that reduction of mitochondrial membrane potential that cannot be controlled by PINK1 signaling initiates metabolic compensation that has neurometabolic consequences relevant to Parkinson disease. PINK1 KO hDANs do not undergo ionophore-induced mitophagy yet CI remains active PINK1 KO impacts the TCA cycle via mAconitase leading to depletion of key amino acids PINK1 KO silences PNPO, which provides essential biological co-factors Dopamine pools and neurotransmitter uptake are reduced by PINK1 loss of function Molecular Biology; Molecular Neuroscience; Stem Cells Research; Omics
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影响因子：
2.5
作者：
Chu CT
通讯作者：
Chu CT
影响因子：
4.5
作者：
Esposito G;Vos M;Vilain S;Swerts J;De Sousa Valadas J;Van Meensel S;Schaap O;Verstreken P
通讯作者：
Verstreken P
影响因子：
14.5
作者：
Fitzgerald, Julia C.;Zimprich, Alexander;Krueger, Rejko
通讯作者：
Krueger, Rejko
影响因子：
5.3
作者：
Anichtchik, Oleg;Diekmann, Heike;Rubinsztein, David C.
通讯作者：
Rubinsztein, David C.
使用 iRT（一种标准化保留时间）可以更有针对性地测量肽。
影响因子：
3.4
作者：
Escher, Claudia;Reiter, Lukas;MacLean, Brendan;Ossola, Reto;Herzog, Franz;Chilton, John;MacCoss, Michael J.;Rinner, Oliver
通讯作者：
Rinner, Oliver