GPR50 regulates neuronal development as a mitophagy receptor

Autor: Ji-Chuan Liu, Xiu-Yun Zhao, Ming-Lei Wu, Yi-fan Shi, Ze-Ping Huang, Li-Pao Fang, Chao Zhu, Xuan Peng, Zi-Ling Shi, Li-Jun Lan, Wen-Li Ji, Li Luo, Lei Feng, Zeng-Li Zhang, De-en Xu, Shao Li, Zheng-Hong Qin, Yan-Yun Sun, Melitta Schachner, Quan-Hong Ma
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Cell Death and Disease, Vol 15, Iss 8, Pp 1-17 (2024)
Druh dokumentu: article
ISSN: 2041-4889
DOI: 10.1038/s41419-024-06978-y
Popis: Abstract Neurons rely heavily on high mitochondrial metabolism to provide sufficient energy for proper development. However, it remains unclear how neurons maintain high oxidative phosphorylation (OXPHOS) during development. Mitophagy plays a pivotal role in maintaining mitochondrial quality and quantity. We herein describe that G protein-coupled receptor 50 (GPR50) is a novel mitophagy receptor, which harbors the LC3-interacting region (LIR) and is required in mitophagy under stress conditions. Although it does not localize in mitochondria under normal culturing conditions, GPR50 is recruited to the depolarized mitochondrial membrane upon mitophagy stress, which marks the mitochondrial portion and recruits the assembling autophagosomes, eventually facilitating the mitochondrial fragments to be engulfed by the autophagosomes. Mutations Δ502-505 and T532A attenuate GPR50-mediated mitophagy by disrupting the binding of GPR50 to LC3 and the mitochondrial recruitment of GPR50. Deficiency of GPR50 causes the accumulation of damaged mitochondria and disrupts OXPHOS, resulting in insufficient ATP production and excessive ROS generation, eventually impairing neuronal development. GPR50-deficient mice exhibit impaired social recognition, which is rescued by prenatal treatment with mitoQ, a mitochondrially antioxidant. The present study identifies GPR50 as a novel mitophagy receptor that is required to maintain mitochondrial OXPHOS in developing neurons.
Databáze: Directory of Open Access Journals
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