title: Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.
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.
authors.affiliation: 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.
authors.forename: Wan Hee
authors.initials: WH
authors.lastname: Yoon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Sandoval
authors.affiliation: 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.
authors.forename: Sonal
authors.initials: S
authors.lastname: Nagarkar-Jaiswal
authors.affiliation: 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.
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.affiliation: 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.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nele A
authors.initials: NA
authors.lastname: Haelterman
authors.affiliation: Department of Molecular and Cellular Biology and Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.affiliation: Department of Molecular and Cellular Biology and Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Vasanta
authors.initials: V
authors.lastname: Putluri
authors.affiliation: Department of Molecular and Cellular Biology and Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: Department of Medical Genetics, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara 06080, Turkey.
authors.forename: Tulay
authors.initials: T
authors.lastname: Tos
authors.affiliation: Department of Child Neurology, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara 06080, Turkey.
authors.forename: Ayse
authors.initials: A
authors.lastname: Aksoy
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Taraka
authors.initials: T
authors.lastname: Donti
authors.affiliation: 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.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Graham
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nishi
authors.affiliation: Department of Pediatric Radiology, Texas Children's Hospital and Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Hunter
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Carmichael
authors.affiliation: Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shen
authors.affiliation: Departments of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Arboleda
authors.affiliation: Departments of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: 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.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wangler
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: 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.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster; D007655:Ketoglutarate Dehydrogenase Complex / Q000235:genetics*; D007656:Ketoglutaric Acids / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018832:Molecular Chaperones; D046912:Multiprotein Complexes / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D007656:Ketoglutaric Acids; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D007655:Ketoglutarate Dehydrogenase Complex; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D008666:Metalloendopeptidases; C087976:nardilysin; D008239:Lysine
keywords: DNAJA3; NRD1; OGDHL; TCA cycle; alpha-ketoglutarate; autophagy; metabolism; mitochondrial chaperones; rapamycin