PINK1/parkin-mediated mitophagy pathway is related to neuroprotection by carnosic acid in SH-SY5Y cells. (March 2019)

• Record Type: Journal Article
• Authors: Lin, Chia-Yuan; Tsai, Chia-Wen
• Is Part Of: Food and chemical toxicology. Volume 125(2019)
• Page Start: 430
• Page End: 437
• Publication Date: 2019-03
• Subjects: Carnosic acid -- PINK1 -- Parkin -- Mitophagy -- SH-SY5Y cells; 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.2019.01.027
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Impairment in mitophagy contributes to the pathology of Parkinson's disease. This study investigated whether Phosphatase and tensin homologue (PTEN)-induced kinase 1 (PINK1)/parkin-mediated mitophagy is linked to the protective effect of carnosic acid (CA) from rosemary. Treatment of SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) disrupted the mitochondrial membrane potential, inhibited voltage-dependent anion channel 1 (VDAC1) protein, and induced cytosolic cytochrome c, but CA pretreatment reversed these findings. By immunofluorescence, CA pretreatment was shown to increase the co-localization of red fluorescence (parkin) and MitoTracker green FM fluorescence (mitochondria), indicating that CA promoted the translocation of parkin into mitochondria. Immunoprecipitation with VDAC1 antibody showed that 6-OHDA treatment decreased the interaction of ubiquitinated protein with VDAC1. However, CA pretreatment reversed this reduction in the interaction of ubiquitinated protein with VDAC1. Silencing of PINK1 and parkin by use of small interfering RNA (siRNA) attenuated the ability of CA to reverse 6-OHDA-inhibited autophagic vacuoles. Moreover, in PINK1 siRNA-transfected cells, CA no longer reversed these actions of 6-OHDA on the inhibition of mitophagy-related proteins (PINK1, parkin, VDAC1, and LC3-II) and anti-apoptotic Bcl-2 protein, as well as the induction of apoptotic-related proteins, and nuclear condensation. In conclusion, CA appears to counteract the neurotoxicity of 6-OHDA by activating PINK1/parkin-mediated mitophagy. Highlights: CA pretreatment protects against 6-OHDA-induced mitochondrial-dependent apoptotic pathway. The clearance of injured mitochondria by CA is involved in the ubiquitination of VDAC1 by activating PINK1/parkin pathway. Knockdown of PINK1 inhibits the reversal of CA on the reduction of mitophagy and the induction of apoptosis by 6-OHDA.