PARK14 PLA2G6 mutants are defective in preventing rotenoneinduced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway

Ching Chi Chiu, Tu Hsueh Yeh, Chin Song Lu, Yin Cheng Huang, Yi Chuan Cheng, Ying Zu Huang, Yi Hsin Weng, Yu Chuan Liu, Szu Chia Lai, Ying Ling Chen, Yu Jie Chen, Chao Lang Chen, Hsin Yi Chen, Yan Wei Lin, Hung Li Wang

研究成果: 雜誌貢獻文章

10 引文 斯高帕斯(Scopus)

摘要

Mutations in the gene encoding Ca2+-independent phospholipase A2 group 6 (PLA2G6) cause the recessive familial type 14 of Parkinson's disease (PARK14). Mitochondrial dysfunction is involved in the pathogenesis of Parkinson's disease (PD). PLA2G6 is believed to be required for maintaining mitochondrial function. In the present study, rotenone-induced cellular model of PD was used to investigate possible molecular pathogenic mechanism of PARK14 mutant PLA2G6-induced PD. Overexpression of wild-type (WT) PLA2G6 ameliorated rotenone-induced apoptotic death of SH-SY5Y dopaminergic cells. PARK14 mutant (D331Y), (G517C), (T572I), (R632W), (N659S) or (R741Q) PLA2G6 failed to prevent rotenone-induced activation of mitochondrial apoptotic pathway and exert a neuroprotective effect. WT PLA2G6, but not PARK14 mutant PLA2G6, prevented rotenone-induced mitophagy impairment. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 was ineffective in attenuating rotenone-induced decrease in mitochondrial membrane potential and increase in the level of mitochondrial superoxide. WT PLA2G6, but not PARK14 PLA2G6 mutants, restored enzyme activity of mitochondrial complex I and cellular ATP content in rotenone-treated SH-SY5Y dopaminergic cells. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 failed to prevent rotenone-induced mitochondrial lipid peroxidation and cytochrome c release. These results suggest that PARK14 PLA2G6 mutants lose their ability to maintain mitochondrial function and are defective inpreventing mitochondrial dysfunction, ROS production and activation of mitochondrial apoptotic pathway in rotenone-induced cellular model of PD.
原文英語
頁(從 - 到)79046-79060
頁數15
期刊Oncotarget
8
發行號45
DOIs
出版狀態已發佈 - 2017

ASJC Scopus subject areas

  • Oncology

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    Chiu, C. C., Yeh, T. H., Lu, C. S., Huang, Y. C., Cheng, Y. C., Huang, Y. Z., Weng, Y. H., Liu, Y. C., Lai, S. C., Chen, Y. L., Chen, Y. J., Chen, C. L., Chen, H. Y., Lin, Y. W., & Wang, H. L. (2017). PARK14 PLA2G6 mutants are defective in preventing rotenoneinduced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway. Oncotarget, 8(45), 79046-79060. https://doi.org/10.18632/oncotarget.20893