Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.
Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.
复制标题
Nardilysin（一种 α-酮戊二酸脱氢酶的线粒体辅助伴侣）的丢失会促进 mTORC1 激活和神经变性。
DOI：
10.1016/j.neuron.2016.11.038
复制
发表时间：
2017-01-04
期刊：
影响因子：
16.2
通讯作者：
Bellen HJ
中科院分区：
文献类型：
--
作者：
Yoon WH;Sandoval H;Nagarkar-Jaiswal S;Jaiswal M;Yamamoto S;Haelterman NA;Putluri N;Putluri V;Sreekumar A;Tos T;Aksoy A;Donti T;Graham BH;Ohno M;Nishi E;Hunter J;Muzny DM;Carmichael J;Shen J;Arboleda VA;Nelson SF;Wangler MF;Karaca E;Lupski JR;Bellen HJ
我们以前在一个正向遗传筛查中发现了纳迪里辛(DNrd1)的突变，该筛查旨在分离那些丢失导致果蝇光感受器神经元神经退化的基因。在这里，我们发现nrd1定位于线粒体，在那里它招募线粒体伴侣并帮助折叠α-酮戊二酸脱氢酶，这是Krebs循环中的限速酶。失去NRd1或OGDH会导致α-酮戊二酸增加，这是OGDHs的底物，进而导致mTORC1激活，从而减少自噬。雷帕霉素抑制mTOR活性或部分恢复自噬可延缓dNrd1突变果蝇的神经变性。综上所述，这项研究揭示了NRD1作为OGDH的线粒体辅助伴侣的新角色，并提供了线粒体代谢障碍、mTORC1信号和神经变性中受损的自噬之间的机制联系。
We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH, and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration.