1. Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration
- Author
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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, and Bellen, Hugo J
- Subjects
Biological Psychology ,Biomedical and Clinical Sciences ,Neurosciences ,Psychology ,Neurodegenerative ,Genetics ,Animals ,Autophagy ,Drosophila ,Drosophila Proteins ,Drosophila melanogaster ,Ketoglutarate Dehydrogenase Complex ,Ketoglutaric Acids ,Lysine ,Mechanistic Target of Rapamycin Complex 1 ,Metalloendopeptidases ,Mitochondria ,Molecular Chaperones ,Multiprotein Complexes ,Neurodegenerative Diseases ,TOR Serine-Threonine Kinases ,DNAJA3 ,NRD1 ,OGDHL ,TCA cycle ,alpha-ketoglutarate ,autophagy ,metabolism ,mitochondrial chaperones ,rapamycin ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
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.
- Published
- 2017