Open AccessPARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway
Author(s) -
Ching-Chi Chiu,
Tu Hsueh Yeh,
Chin Song Lu,
Yin Huang,
Cheng Yi,
Ying Huang,
Yueh-Hsuan Weng,
Yu Chuan Liu,
ShenHao Lai,
Ying Ling Chen,
Yu Jie Chen,
Chao Lang Chen,
Hsin Yi Chen,
Lin Yan,
Hung Li Wang
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.20893
Subject(s) - rotenone , apoptosis , mitochondrion , mutant , reactive oxygen species , microbiology and biotechnology , mitochondrial ros , mitochondrial dna , medicine , biology , genetics , gene
Mutations in the gene encoding Ca 2+ -independent phospholipase A 2 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.