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Neuron. 2017 Jan 4;93(1):115-131. doi: 10.1016/j.neuron.2016.11.038. Epub 2016 Dec 22.

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

Author information

1
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.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
4
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
5
Department of Molecular and Cellular Biology and Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Medical Genetics, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara 06080, Turkey.
7
Department of Child Neurology, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara 06080, Turkey.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
9
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, Baylor College of Medicine, Houston, TX 77030, USA.
10
Department of Pediatric Radiology, Texas Children's Hospital and Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
11
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
12
Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
13
Departments of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
14
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
15
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; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.

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.

KEYWORDS:

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

PMID:
28017472
PMCID:
PMC5242142
DOI:
10.1016/j.neuron.2016.11.038
[Indexed for MEDLINE]
Free PMC Article

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