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FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome.
Chen, Yingji; Jiao, Dongyue; Liu, Yang; Xu, Xiayun; Wang, Yilin; Luo, Xiaona; Saiyin, Hexige; Li, Yao; Gao, Kun; Chen, Yucai; Zhao, Shi-Min; Ma, Lixiang; Wang, Chenji.
Afiliación
  • Chen Y; Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, PR China.
  • Jiao D; Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, PR China.
  • Liu Y; Department of Anatomy, Histology & Embryology, School of Basic Medical Science, Fudan University, Shanghai, PR China.
  • Xu X; Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, PR China.
  • Wang Y; Department of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, PR China.
  • Luo X; Department of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, PR China.
  • Saiyin H; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, PR China.
  • Li Y; Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, PR China.
  • Gao K; Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, PR China.
  • Chen Y; Department of Neurology, Shanghai Children's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai, PR China. chenyc@shchildren.com.cn.
  • Zhao SM; Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, PR China. zhaosm@fudan.edu.cn.
  • Ma L; Department of Anatomy, Histology & Embryology, School of Basic Medical Science, Fudan University, Shanghai, PR China. lxma@fudan.edu.cn.
  • Wang C; Obstetrics & Gynecology Hospital of Fudan University, Institutes of Metabolism and Integrative Biology, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, PR China. chenjiwang@fudan.edu.cn.
Cell Death Differ ; 30(10): 2351-2363, 2023 Oct.
Article en En | MEDLINE | ID: mdl-37568009
Mitochondria are essential organelles found in eukaryotic cells that play a crucial role in ATP production through oxidative phosphorylation (OXPHOS). Mitochondrial DNA depletion syndrome (MTDPS) is a group of genetic disorders characterized by the reduction of mtDNA copy number, leading to deficiencies in OXPHOS and mitochondrial functions. Mutations in FBXL4, a substrate-binding adaptor of Cullin 1-RING ubiquitin ligase complex (CRL1), are associated with MTDPS, type 13 (MTDPS13). Here, we demonstrate that, FBXL4 directly interacts with the mitophagy cargo receptors BNIP3 and BNIP3L, promoting their degradation through the ubiquitin-proteasome pathway via the assembly of an active CRL1FBXL4 complex. However, MTDPS13-associated FBXL4 mutations impair the assembly of an active CRL1FBXL4 complex. This results in a notable accumulation of BNIP3/3L proteins and robust mitophagy even at basal levels. Excessive mitophagy was observed in Knockin (KI) mice carrying a patient-derived FBXL4 mutation and cortical neurons (CNs)-induced from MTDPS13 patient human induced pluripotent stem cells (hiPSCs). In summary, our findings suggest that abnormal activation of BNIP3/BNIP3L-dependent mitophagy impairs mitochondrial homeostasis and underlies FBXL4-mutated MTDPS13.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Death Differ Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Death Differ Año: 2023 Tipo del documento: Article Pais de publicación: Reino Unido