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

Wan Hee Yoon, Hector Sandoval, Sonal Nagarkar-Jaiswal, Manish Jaiswal, Shinya Yamamoto, Nele A. Haelterman, Nagireddy Putluri, Vasanta Putluri, Arun Sreekumar, Tulay Tos, Ayse Aksoy, Taraka Donti, Brett H. Graham, Mikiko Ohno, Eiichiro Nishi, Jill Hunter, Donna M. Muzny, Jason Carmichael, Joseph Shen, Valerie A. ArboledaStanley F. Nelson, Michael F. Wangler, Ender Karaca, James R. Lupski, Hugo J. Bellen

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)115-131
Number of pages17
JournalNeuron
Volume93
Issue number1
DOIs
StatePublished - Jan 4 2017

Keywords

  • alpha-ketoglutarate
  • autophagy
  • DNAJA3
  • metabolism
  • mitochondrial chaperones
  • NRD1
  • OGDHL
  • rapamycin
  • TCA cycle

ASJC Scopus subject areas

  • Neuroscience(all)

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