ArticleNeuron2017
Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration.
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Article in Neuron, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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78citing papers in PubMed
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Who cites it
78 citing papers in PubMed, 109 citations in OpenAlex.
- Pathogenic mutations in ATAD3A cause dysregulation of RagC/D-TFEB axis and disrupt lysosomal homeostasis.bioRxiv : the preprint server for biology · 2026Article
- Nardilysin regulatesBiochemistry and biophysics reports · 2026Article
- HeterozygousJIMD reports · 2026Article
- Inferring Patterns of Purifying, Positive, and Balancing Selection in the Coppery Titi Monkey (Plecturocebus cupreus) Utilizing a Well-Fit Evolutionary Baseline Model.Genome biology and evolution · 2026Article
- Bi-allelic variants in NRDC cause a neurodevelopmental disorder characterized by neonatal lethality, microcephaly, and brain abnormalities.American journal of human genetics · 2026Article
- Article
- Exercise training-induced extracellular miR-136-3p modulates glucose uptake and myogenesis through targeting of NRDC in human skeletal muscle.Journal of sport and health science · 2025Article
- Targeted Redox Regulation α-Ketoglutarate Dehydrogenase Complex for the Treatment of Human Diseases.Cells · 2025Review
- Impacts of mitochondrial dysfunction on axonal microtubule bundles as a potential mechanism of neurodegeneration.Frontiers in neuroscience · 2025Review
- TCA metabolism regulates DNA hypermethylation in LPS andProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation.Brain : a journal of neurology · 2024Article
- Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.Nature communications · 2024Article
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
- The alpha-ketoacid dehydrogenase complexes ofmicroPublication biology · 2024Article
- Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity.Genome medicine · 2023Article
- A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.Nature metabolism · 2023Article
- The oxoglutarate dehydrogenase complex is involved in myofibril growth and Z-disc assembly in Drosophila.Journal of cell science · 2023Article
- Biallelic variants in OGDH encoding oxoglutarate dehydrogenase lead to a neurodevelopmental disorder characterized by global developmental delay, movement disorder, and metabolic abnormalities.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Genome- and Exome-Wide Association Studies Revealed Candidate Genes Associated with DaTscan Imaging Features.Parkinson's disease · 2023Article
- Review
18 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 7 institutions in 3 countries.
Wan Hee YoonHoward 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.
Hector SandovalDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Sonal Nagarkar-JaiswalHoward 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.
Manish JaiswalHoward 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.
Shinya YamamotoDepartment 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.
Nele A HaeltermanProgram in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Nagireddy PutluriDepartment of Molecular and Cellular Biology and Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
Vasanta PutluriDepartment of Molecular and Cellular Biology and Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
Arun SreekumarDepartment of Molecular and Cellular Biology and Advanced Technology Core, Baylor College of Medicine, Houston, TX 77030, USA.
Tulay TosDepartment of Medical Genetics, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara 06080, Turkey.
Ayse AksoyDepartment of Child Neurology, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara 06080, Turkey.
Taraka DontiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Brett H GrahamDepartment 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.
Mikiko OhnoDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, Baylor College of Medicine, Houston, TX 77030, USA.
Eiichiro NishiDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, Baylor College of Medicine, Houston, TX 77030, USA.
Jill HunterDepartment of Pediatric Radiology, Texas Children's Hospital and Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA.
Donna M MuznyHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jason CarmichaelMedical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
Joseph ShenMedical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
Valerie A ArboledaDepartments of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Stanley F NelsonDepartments of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Michael F WanglerDepartment 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.
Ender KaracaDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
James R LupskiDepartment 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.
Hugo J BellenHoward 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.
Baylor College of Medicine · USChildren's Hospital Central California · USHoward Hughes Medical Institute · USTexas Children's Hospital · USUniversity of California, Los Angeles · USMinistry of Health · TRNeurological Research Institute · US
Funding
Tumor BiologyP30CA125123 · NCI · BAYLOR COLLEGE OF MEDICINE · PI DAVID R ROWLEY · 2007 to 2026
$73.9MTransposon induced disruption of most Drosophila genesR01GM067858 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J · 2003 to 2020
$15.7MBaylor-Johns Hopkins Center for Mendelian GeneticsU54HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2012 to 2015
$15.6MResearch Education and Career Horizons ProgramK12GM084897 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI SIFERS, RICHARD NORMAN, SLAUGHTER, GAYLE · 2008 to 2016
$8.3MSteps towards a paternal gene activation therapy for Angelman syndromeU54HD083092 · NICHD · BAYLOR COLLEGE OF MEDICINE · PI NELSON, DAVID LOREN, SAMACO, RODNEY C · 2014 to 2019
$7.8MNonrecurrent rearrangements, genome architecture and neurodegenerative disease.R01NS058529 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2009 to 2017
$5.0MGenomic medicine and gene function implementation for an underserved populationR01HG011795 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J, WANGLER, MICHAEL FRANCIS · 2021 to 2025
$4.8MMutidisciplinary Training;Brain Disorders &DevelopmentT32NS043124 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI SWANN, JOHN WILLIAM · 2002 to 2021
$4.6MMapping and rescuing EMS-induced lethal mutations on the Drosophila X ChromosomeRC4GM096355 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI BELLEN, HUGO J · 2010 to 2010
$1.7MSuccinyl-COA Synthetase Deficiency: A Model to Study Mitochondrial DNA (MTDNA) DeR01GM098387 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI GRAHAM, BRETT HARRISON · 2012 to 2016
$1.5MNeuronal Mechanisms of Peroxisomal Biogenesis Defects in DrosophilaK08NS076547 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI WANGLER, MICHAEL FRANCIS · 2011 to 2015
$729kHoward Hughes Medical InstituteNCI NIH HHS P30 CA125123NHGRI NIH HHS R01 HG011795NHGRI NIH HHS U54 HG006542NICHD NIH HHS U54 HD083092NIGMS NIH HHS K12 GM084897NIGMS NIH HHS R01 GM067858NIGMS NIH HHS R01 GM098387NIGMS NIH HHS RC4 GM096355NINDS NIH HHS K08 NS076547NINDS NIH HHS R01 NS058529NINDS NIH HHS T32 NS043124
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.
Indexed as
AnimalsAutophagyDrosophilaDrosophila melanogasterDrosophila ProteinsKetoglutarate Dehydrogenase ComplexKetoglutaric AcidsLysineMechanistic Target of Rapamycin Complex 1MetalloendopeptidasesMitochondriaMolecular ChaperonesMultiprotein ComplexesNeurodegenerative DiseasesTOR Serine-Threonine KinasesDrosophila ProteinsKetoglutarate Dehydrogenase ComplexKetoglutaric AcidsLysineMechanistic Target of Rapamycin Complex 1MetalloendopeptidasesMolecular ChaperonesMultiprotein ComplexesnardilysinTOR Serine-Threonine Kinasesalpha-ketoglutarateautophagyDNAJA3metabolismmitochondrial chaperonesNRD1OGDHLrapamycinTCA cycle
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