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Baylor College of Medicine

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Neuron, Available online 22 December 2016 | http://dx.doi.org/10.1016/j.neuron.2016.11.038 Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration

Abstract

Wan Hee Yoon^{1, 2}, Hector Sandoval², Sonal Nagarkar-Jaiswal^{1, 2}, Manish Jaiswal^{1, 2}, Shinya Yamamoto^{2, 3, 4}, Nele A. Haelterman³, Nagireddy Putluri⁵, Vasanta Putluri⁵, Arun Sreekumar⁵, Tulay Tos⁶, Ayse Aksoy⁷, Taraka Donti², Brett H. Graham^{2, 3}, Mikiko Ohno⁸, Eiichiro Nishi⁸, Jill Hunter⁹, Donna M. Muzny¹⁰, Jason Carmichael¹¹, Joseph Shen¹¹, Valerie A. Arboleda¹², Stanley F. Nelson¹², Michael F. Wangler^{2, 3, 4}, Ender Karaca², James R. Lupski^{2, 10, 13}, Hugo J. Bellen^{1, 2, 3, 4, 14, 15,*}

¹ Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
²Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
³ Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
⁴Jan and Duncan Neurological Research Institute, Texas Children’s Hospital, 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
⁷Department 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 Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan, Baylor College of Medicine, Houston, TX 77030, USA
⁹ Department of Pediatric Radiology, Texas Children’s Hospital and Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA
¹⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
¹¹Medical Genetics and Metabolism, Valley Children’s Hospital, Madera, CA 93636, USA
¹² Departments of Human Genetics and Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
¹³ Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA
¹⁴ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA
¹⁵ Lead Contact

Corresponding author

Summary
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: metabolism, alpha-ketoglutarate, mitochondrial chaperones, TCA cycle, OGDHL, NRD1, DNAJA3, autophagy, rapamycin

논문정보

형식Research article
게재일2016년 12월 (BRIC 등록일 2016-12-27)
연구진국외 연구진
분야 생명과학 > 유전학

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