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

Qingxi Zhang; Yin Huang; Anbiao Wu; Qingrui Duan; Peikun He; Haifeng Huang; Yuyuan Gao; Kun Nie; Qicai Liu; Lijuan Wang

doi:10.1016/j.biocel.2023.106385

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

Int J Biochem Cell Biol. 2023 Apr:157:106385. doi: 10.1016/j.biocel.2023.106385. Epub 2023 Feb 7.

Authors

Qingxi Zhang¹, Yin Huang², Anbiao Wu³, Qingrui Duan⁴, Peikun He⁴, Haifeng Huang⁴, Yuyuan Gao⁴, Kun Nie⁴, Qicai Liu⁵, Lijuan Wang⁶

Affiliations

¹ Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China; Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Guangzhou Key Laboratory of Diagnosis and Treatment for Neurodegenerative Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
² The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.
³ Department of Cardiology, Laboratory of Heart Center; Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
⁴ Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Guangzhou Key Laboratory of Diagnosis and Treatment for Neurodegenerative Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
⁵ Department of Cardiology, Laboratory of Heart Center; Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. Electronic address: liuqicai968@smu.edu.cn.
⁶ Department of Neurology, Guangdong Neuroscience Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Guangzhou Key Laboratory of Diagnosis and Treatment for Neurodegenerative Diseases, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China. Electronic address: wljgd68@163.com.

PMID: 36754160
DOI: 10.1016/j.biocel.2023.106385

Abstract

α-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 α-synuclein phosphorylation on mitochondrial calcium influx and mitochondrial function in Parkinson's disease. The function of the key phosphokinase, 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 α-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 α-synuclein to activate mitochondrial calcium uniporter and thus increase mitochondrial calcium influx, and these effects were blocked by α-synuclein S129A mutant expression. Furthermore, the calcium/calmodulin-dependent serine protein kinase inhibitor CASK-IN-1 exerted neuroprotective effects in Parkinson's disease. Collectively, our results suggest that calcium/calmodulin-dependent serine protein kinase phosphorylates α-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.

Keywords: Calcium/calmodulin-dependent serine protein kinase; Mitochondrial calcium uniporter; Parkinson’s disease; α-synuclein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcium / metabolism
Calmodulin / metabolism
Humans
Parkinson Disease* / metabolism
Protein Kinases / metabolism
Serine
alpha-Synuclein

Substances

alpha-Synuclein
mitochondrial calcium uniporter
Calmodulin
Calcium
Protein Kinases
Serine