Upregulation of OPA1 by carnosic acid is mediated through induction of IKKγ ubiquitination by parkin and protects against neurotoxicity. (February 2020)

• Record Type: Journal Article
• Authors: Lin, Chia-Yuan; Chen, Wen-Jiun; Fu, Ru-Huei; Tsai, Chia-Wen
• Is Part Of: Food and chemical toxicology. Volume 136(2020)
• Publication Date: 2020-02
• Subjects: Carnosic acid -- 6-hydroxydopamine -- Mitochondrial dynamics -- Optic atrophy 1 -- Parkin/IKKγ/p65 pathway; 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.2019.110942
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: An imbalance in mitochondrial dynamics is strongly associated with Parkinson's disease. The fusion protein optic atrophy 1 (OPA1) is up-regulated through the activation of parkin-mediated IκB kinase γ (IKKγ)/p65 signaling. This study investigated whether the neuroprotection of carnosic acid (CA) from rosemary is involved in mitochondrial dynamics and OPA1 protein induction by parkin/IKKγ/p65 signaling. The neurotoxin 6-hydroxydopamine (6-OHDA) treated with SH-SY5Y cells decreased OPA1 and mitofusin 2 fusion proteins, but increased fission 1 and dynamin related protein 1 (DRP1) fission proteins. By immunofluorescence, 6-OHDA induced the fluorescence of green spots outside the mitochondria, indicating that cytochrome c was released to the cytoplasm. Except for the effects on DRP1 protein, CA pretreatment reversed these effects of 6-OHDA. Additionally, CA treatment increased the ubiquitination of IKKγ, nuclear p65 protein, OPA1-p65 DNA binding activity, and OPA1 protein. However, transfection of parkin small interfering RNA (siRNA) attenuated these effects of CA. Furthermore, transfection of OPA1 siRNA abolished the action of CA to reverse 6-OHDA-increased cytosolic cytochrome c protein, apoptotic-related protein cleavage, and cell death. In conclusion, the mechanism by which CA counteracts the toxicity of 6-OHDA is through modulation of mitochondrial dynamics and upregulation of OPA1 via activation of the parkin/IKKγ/p65 pathway. Highlights: Pretreatment of CA attenuated the change of mitochondrial fission and fusion by 6-OHDA. The up-regulation of OPA1 induced by CA is associated with the activation of the parkin/IKKγ/p65 pathway. Silencing of OPA1 inhibited the ability of CA to reverse the toxicity of 6-OHDA.