Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.
Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.
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DOI：
10.1073/pnas.2009838117
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发表时间：
2020-10-20
影响因子：
11.1
通讯作者：
Murphy CT
中科院分区：
文献类型：
--
作者：
Mor DE;Sohrabi S;Kaletsky R;Keyes W;Tartici A;Kalia V;Miller GW;Murphy CT
发现代谢缺陷在帕金森氏病(PD)中的作用可能会导致发现疾病修改疗法。我们最近将支链氨基酸(BCAA)代谢与帕金森病联系起来，但其潜在机制尚不清楚。我们现在报告一项意想不到的发现，支链氨基酸代谢障碍通过诱导线粒体过度活跃而导致帕金森样运动障碍和神经变性。我们发现，治疗2型糖尿病的药物二甲双胍能够通过减少线粒体呼吸来挽救神经元的存活。这些结果提供了线粒体过度活跃作为帕金森病线粒体功能障碍的一种新的潜在机制，并表明在疾病早期减少线粒体呼吸的努力-可能通过二甲双胍治疗-可能是有效的。代谢功能障碍发生在许多与年龄相关的神经退行性疾病中，但其在疾病病因学中的作用尚不清楚。我们最近发现支链氨基酸转移酶BCAT-1与神经退行性运动障碍帕金森病(PD)之间存在潜在的因果联系。RNAi介导的秀丽线虫BCAT-1基因敲除已知可概括帕金森病样特征，包括进行性运动缺陷和随年龄增长的神经变性，但其潜在机制尚不清楚。利用转录、代谢和成像方法，我们在这里展示了BCAT-1基因敲除通过哺乳动物雷帕霉素非依赖性机制增加线粒体呼吸和诱导神经元氧化损伤。BCAT-1(RNAi)神经毒性需要增加线粒体呼吸或“线粒体过度活动”。此外，我们发现，发病后服用2型糖尿病药物二甲双胍可将线粒体呼吸降低到控制水平，并显著改善运动功能和神经元活性。综上所述，我们的发现提示线粒体过度活跃可能是帕金森病发病机制中的早期事件，旨在减少线粒体呼吸的策略可能构成治疗帕金森病的一条令人惊讶的新途径。
Uncovering the role of defective metabolism in Parkinson’s disease (PD) may lead to the discovery of disease-modifying therapies. We recently linked branched-chain amino acid (BCAA) metabolism with PD, yet the underlying mechanisms were unknown. We now report the unexpected finding that BCAA metabolic dysfunction causes Parkinson’s-like motor deficits and neurodegeneration by inducing a state of hyperactive mitochondria. We found that the type 2 diabetes medication metformin is able to rescue neuronal viability by reducing mitochondrial respiration. These results offer mitochondrial hyperactivity as a new potential mechanism of mitochondrial dysfunction in Parkinson’s disease, and suggest that efforts to reduce mitochondrial respiration early in the disease—potentially by metformin treatment—may be efficacious. Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase BCAT-1 and the neurodegenerative movement disorder Parkinson’s disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here that bcat-1 knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or “mitochondrial hyperactivity,” is required for bcat-1(RNAi) neurotoxicity. Moreover, we show that post–disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.
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影响因子：
4.6
作者：
Luan H;Liu LF;Tang Z;Zhang M;Chua KK;Song JX;Mok VC;Li M;Cai Z
通讯作者：
Cai Z
影响因子：
5.4
作者：
Klein, Christine;Westenberger, Ana
通讯作者：
Westenberger, Ana
影响因子：
7.8
作者：
Goudeau, Jerome;Aguilaniu, Hugo
通讯作者：
Aguilaniu, Hugo
影响因子：
3.3
作者：
Corsi AK;Wightman B;Chalfie M
通讯作者：
Chalfie M
DOI：
10.1097/jom.0000000000000773
发表时间：
2016-08
影响因子：
3.2
作者：
Liu KH;Walker DI;Uppal K;Tran V;Rohrbeck P;Mallon TM;Jones DP
通讯作者：
Jones DP