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Carnosic acid depends on glutathione to promote mitochondrial protection in methylglyoxal-exposed SH-SY5Y cells

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Abstract

Methylglyoxal (MG) is an endogenously produced toxicant that induces mitochondrial dysfunction leading to impaired redox biology homeostasis, bioenergetics collapse, and cell death in mammalian cells. However, MG toxicity is particularly relevant to neurons and glia given their chemical and metabolic characteristics. Here, we have investigated whether a pretreatment with carnosic acid (CA) would be able to promote mitochondrial protection in human neuroblastoma SH-SY5Y cells exposed to MG. We found that a pretreatment with CA at 1 μM for 12 h prevented the MG-induced lipid peroxidation and protein carbonylation and nitration in the membranes of mitochondria obtained from the SH-SY5Y cells. CA also prevented the MG-elicited Complexes I and V dysfunction, adenosine triphosphate (ATP) levels decline, and loss of mitochondrial membrane potential (MMP). Moreover, CA also reduced the mitochondrial production of the radical anion superoxide (O2−•) in the MG-challenged cells. We found that CA upregulated the synthesis of glutathione (GSH) by increasing the activity of the γ-glutamylcysteine ligase (γ-GCL). Inhibition of the GSH synthesis by buthionine sulfoximine (BSO) abolished the CA-induced mitochondrial protection. Besides, inhibition of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, as well as silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), suppressed the CA-stimulated protection and the synthesis of GSH. Thus, CA promoted mitochondrial protection by a PI3K/Akt/Nrf2/γ-GCL/GSH axis in MG-treated SH-SY5Y cells.

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All data generated or analysed during this study are included in this published article (and its supplementary information files).

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Acknowledgements

MRO receives a “Bolsa de Produtividade em Pesquisa 2 – PQ2” fellow from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) (protocol number 301273/2018-9). This work received financial support from CNPq (protocol numbers 400216/2016-7 and 460903/2014-4).

Funding

This study was funded by Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq) [grant number 301273/2018-9 (Bolsa de Produtividade em Pesquisa 2 – PQ2), grant number 400216/2016-7, and grant number 460903/2014-4].

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Conceptualization: Marcos Roberto de Oliveira; Methodology: Izabel Cristina Custodio de Souza, Rênata Cristina Bertolini Gobbo, Fhelipe Jolner Souza de Almeida, Matheus Dargesso Luckachaki, Marcos Roberto de Oliveira; Formal analysis and investigation: Izabel Cristina Custodio de Souza, Rênata Cristina Bertolini Gobbo, Fhelipe Jolner Souza de Almeida, Matheus Dargesso Luckachaki, Marcos Roberto de Oliveira; Writing - original draft preparation: Marcos Roberto de Oliveira; Writing - review and editing: Izabel Cristina Custodio de Souza, Rênata Cristina Bertolini Gobbo, Fhelipe Jolner Souza de Almeida, Matheus Dargesso Luckachaki, Marcos Roberto de Oliveira; Funding acquisition: Marcos Roberto de Oliveira and Izabel Cristina Custodio de Souza; Resources: Marcos Roberto de Oliveira and Izabel Cristina Custodio de Souza; Supervision: Marcos Roberto de Oliveira.

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Correspondence to Marcos Roberto de Oliveira.

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de Souza, I.C.C., Gobbo, R.C.B., de Almeida, F.J.S. et al. Carnosic acid depends on glutathione to promote mitochondrial protection in methylglyoxal-exposed SH-SY5Y cells. Metab Brain Dis 36, 471–481 (2021). https://doi.org/10.1007/s11011-020-00651-x

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  • DOI: https://doi.org/10.1007/s11011-020-00651-x

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