Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.

TitleLoss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.
Publication TypeJournal Article
Year of Publication2017
AuthorsYoon, WHee, 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
JournalNeuron
Volume93
Issue1
Pagination115-131
Date Published2017 Jan 04
ISSN1097-4199
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.

DOI10.1016/j.neuron.2016.11.038
Alternate JournalNeuron
PubMed ID28017472
PubMed Central IDPMC5242142
Grant ListK08 NS076547 / NS / NINDS NIH HHS / United States
K12 GM084897 / GM / NIGMS NIH HHS / United States
R01 GM098387 / GM / NIGMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
RC4 GM096355 / GM / NIGMS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
R01 GM067858 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States