Calcium/calmodulin-dependent serine protein kinase exacerbates mitochondrial calcium uniporter-related mitochondrial calcium overload by phosphorylating α-synuclein in Parkinson's disease

被引：7
作者：
Zhang, Qingxi [1 ,2 ,3 ]
Huang, Yin [4 ]
Wu, Anbiao [5 ,6 ]
Duan, Qingrui [2 ,3 ]
He, Peikum [2 ,3 ]
Huang, Haifeng [2 ,3 ]
Gao, Yuyuan [2 ,3 ]
Nie, Kun [2 ,3 ]
Liu, Qicai [5 ,6 ]
Wang, Lijuan [2 ,3 ]
机构：
[1] Guangdong Prov Peoples Hosp, Guangdong Cardiovasc Inst, Guangdong Acad Med Sci, Guangzhou 510100, Peoples R China
[2] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Neurosci Inst, Guangdong Acad Med Sci,Dept Neurol, Guangzhou 510080, Peoples R China
[3] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Guangzhou Key Lab Diag & Treatment Neurodegenerat, Guangzhou 510080, Peoples R China
[4] Southern Med Univ, Sch Clin Med 2, Guangzhou 510515, Peoples R China
[5] Southern Med Univ, Lab Heart Ctr, Dept Cardiol, Guangzhou 510280, Peoples R China
[6] Southern Med Univ, Zhujiang Hosp, Guangdong Prov Biomed Engn Technol Res Ctr Cardiov, Guangzhou 510280, Peoples R China
来源：
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY | 2023年 / 157卷
关键词：
Parkinson?s disease; -synuclein; Calcium; calmodulin-dependent serine protein; kinase; Mitochondrial calcium uniporter; SER129; NEURODEGENERATION; PATHOGENESIS; MEMBRANE; CELLS; MCU;
D O I：
10.1016/j.biocel.2023.106385
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
alpha-Synuclein phosphorylation and mitochondrial calcium homeostasis are important mechanisms underlying mitochondrial dysfunction in Parkinson's disease, but the network regulating these mechanisms remains unclear. We identified the role of key phosphokinases and the pathological effects of alpha-synuclein phosphorylation on mitochondrial calcium influx and mitochondrial function in Parkinson's disease. The function of the key phos-phokinase, calcium/calmodulin-dependent serine protein kinase, was investigated through loss-and gain-of-function experiments using a cell model of Parkinson's disease. The regulation of mitochondrial calcium uniporter-mediated mitochondrial calcium influx by calcium/calmodulin-dependent serine protein kinase was explored using a cellular model of Parkinson's disease. Coimmunoprecipitation experiments and alpha-synuclein mutation were used to explore the mechanism through which calcium/calmodulin-dependent serine protein kinase regulates mitochondrial calcium uniporter-mediated mitochondrial calcium influx and exacerbates mitochondrial damage in Parkinson's disease. Here, we show the pathogenic role of calcium/calmodulin-dependent serine protein kinase in Parkinson's disease progression. Calcium/calmodulin-dependent serine protein kinase phosphorylated alpha-synuclein to activate mitochondrial calcium uniporter and thus increase mitochondrial calcium influx, and these effects were blocked by alpha-synuclein S129A mutant expression. Furthermore, the calcium/calmodulin-dependent serine protein kinase inhibitor CASK-IN-1 exerted neuro-protective effects in Parkinson's disease. Collectively, our results suggest that calcium/calmodulin-dependent serine protein kinase phosphorylates alpha-synuclein to activate the mitochondrial calcium uniporter and thereby causes mitochondrial calcium overload and mitochondrial damage in Parkinson's disease. We elucidated a new role of calcium/calmodulin-dependent serine protein kinase in Parkinson's disease and revealed the potential therapeutic value of targeting calcium/calmodulin-dependent serine protein kinase in Parkinson's disease treatment.
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页数：13
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