Yoon Wan Hee, Sandoval Hector, Nagarkar-Jaiswal Sonal, Jaiswal Manish, Yamamoto Shinya, Haelterman Nele A, Putluri Nagireddy, Putluri Vasanta, Sreekumar Arun, Tos Tulay, Aksoy Ayse, Donti Taraka, Graham Brett H, Ohno Mikiko, Nishi Eiichiro, Hunter Jill, Muzny Donna M, Carmichael Jason, Shen Joseph, Arboleda Valerie A, Nelson Stanley F, Wangler Michael F, Karaca Ender, Lupski James R, Bellen Hugo J
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Neuron. 2017 Jan 4;93(1):115-131. doi: 10.1016/j.neuron.2016.11.038. Epub 2016 Dec 22.
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.
我们之前在一项正向遗传学筛选中鉴定出了Nardilysin（dNrd1）中的突变，该筛选旨在分离那些缺失会导致果蝇光感受器神经元神经退行性变的基因。在此我们表明，NRD1定位于线粒体，在那里它招募线粒体伴侣蛋白并协助α-酮戊二酸脱氢酶（OGDH，三羧酸循环中的一种限速酶）的折叠。Nrd1或Ogdh的缺失会导致OGDH的底物α-酮戊二酸增加，进而导致mTORC1激活以及随后自噬的减少。用雷帕霉素抑制mTOR活性或部分恢复自噬可延缓dNrd1突变果蝇的神经退行性变。总之，本研究揭示了NRD1作为OGDH的线粒体共伴侣蛋白的新作用，并提供了线粒体代谢功能障碍、mTORC1信号传导和神经退行性变中自噬受损之间的机制联系。
