Carnosic acid attenuated cytochrome c release through the mitochondrial structural protein Mic60 by PINK1 in SH-SY5Y cells. (March 2023)

• Record Type: Journal Article
• Authors: Lin, Chia-Yuan; Huang, Yi-Chen; Wu, Chi-Rei; Wu, Han-Ting; Fu, Ru-Huei; Tsai, Chia-Wen
• Is Part Of: Food and chemical toxicology. Volume 173(2023)
• Publication Date: 2023-03
• Subjects: Carnosic acid -- Mic60 -- PKA -- PINK1-mediated mitophagy -- Parkinson's disease; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2023.113636
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Mitochondrial dysfunction has been implicated in Parkinson's disease. Mic60 is a critical component of mitochondrial crista remodeling and participates in maintaining mitochondrial structure and function. This study investigated whether the carnosic acid (CA) of rosemary protects the mitochondria of SH-SY5Y cells against the neurotoxicity of 6-hydroxydopamine (6-OHDA) by regulating Mic60. Our results showed that CA pretreatment reversed the reduction in the Mic60 and citrate synthase proteins, as well as the protein induction of PKA caused by 6-OHDA. Moreover, Mic60 and PINK1 siRNAs blocked the ability of CA to lessen the release of mitochondrial cytochrome c by 6-OHDA. As shown by immunoprecipitation assay, in 6-OHDA-treated cells, the interaction of Mic60 with its phosphorylated threonine residue was decreased, but the interaction with its phosphorylated serine residue was increased. PINK1 siRNA and forskolin, a PKA activator, reversed these interactions. Moreover, forskolin pretreatment prevented CA from rescuing the interaction of PINK1 and Mic60 and the reduction in cytochrome c release and mitophagy impairment in 6-OHDA-treated cells. In conclusion, CA prevents 6-OHDA-induced cytochrome c release by regulating Mic60 phosphorylation by PINK1 through a downregulation of PKA. The regulation of Mic60 by CA can be considered as a protective mechanism for the prevention of Parkinson's disease. Highlights: CA improved 6-OHDA-induced mitochondrial cytochrome c release by Mic60. CA increased the Mic60 phosphorylation at threonine residue by PINK1. CA blocked 6-OHDA-activated PKA by reducing the Mic60 phosphorylation at serine. CA rescued 6-OHDA-induced mitophagy impairment through inhibiting PKA by PINK1.