Loss of function of CMPK2 causes mitochondria deficiency and brain calcification
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Published:2022-11-29
Issue:1
Volume:8
Page:
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ISSN:2056-5968
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Container-title:Cell Discovery
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language:en
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Short-container-title:Cell Discov
Author:
Zhao Miao, Su Hui-Zhen, Zeng Yi-Heng, Sun Yuan, Guo Xin-Xin, Li Yun-Lu, Wang Chong, Zhao Zhi-Yuan, Huang Xue-Jing, Lin Kai-Jun, Ye Zi-Ling, Lin Bi-Wei, Hong Shunyan, Zheng Jitan, Liu Yao-Bin, Yao Xiang-Ping, Yang Dehao, Lu Ying-Qian, Chen Hai-Zhu, Zuo Erwei, Yang Guang, Wang Hong-Tao, Huang Chen-Wei, Lin Xiao-Hong, Cen Zhidong, Lai Lu-Lu, Zhang Yan-Ke, Li Xi, Lai Tianmin, Lin Jingjing, Zuo Dan-Dan, Lin Min-Ting, Liou Chia-Wei, Kong Qing-Xia, Yan Chuan-Zhu, Xiong Zhi-Qi, Wang Ning, Luo Wei, Zhao Cui-Ping, Cheng XuewenORCID, Chen Wan-Jin
Abstract
AbstractBrain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Genetics,Molecular Biology,Biochemistry
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