title: Carnosic Acid Suppresses the H2O2-Induced Mitochondria-Related Bioenergetics Disturbances and Redox Impairment in SH-SY5Y Cells: Role for Nrf2.
abstract: The phenolic diterpene carnosic acid (CA, C20H28O4) exerts antioxidant, anti-inflammatory, anti-apoptotic, and anti-cancer effects in mammalian cells. CA activates the nuclear factor erythroid 2-related factor 2 (Nrf2), among other signaling pathways, and restores cell viability in several in vitro and in vivo experimental models. We have previously reported that CA affords mitochondrial protection against various chemical challenges. However, it was not clear yet whether CA would prevent chemically induced impairment of the tricarboxylic acid cycle (TCA) function in mammalian cells. In the present work, we found that a pretreatment of human neuroblastoma SH-SY5Y cells with CA at 1 μM for 12 h prevented the hydrogen peroxide (H2O2)-induced impairment of the TCA enzymes (aconitase, α-ketoglutarate dehydrogenase (α-KGDH), succinate dehydrogenase (SDH)) and abolished the inhibition of the complexes I and V and restored the levels of ATP by a mechanism associated with Nrf2. CA also exhibited antioxidant abilities by enhancing the levels of reduced glutathione (GSH) and decreasing the content oxidative stress markers (cellular 8-oxo-2'-deoxyguanosine (8-oxo-dG), and mitochondrial malondialdehyde (MDA), protein carbonyl, and 3-nitrotyrosine). Silencing of Nrf2 by small interfering RNA (siRNA) abrogated the protective effects elicited by CA in mitochondria of SH-SY5Y cells. Therefore, CA prevented the H2O2-triggered mitochondrial impairment by an Nrf2-dependent mechanism. The specific role of Nrf2 in ameliorating the function of TCA enzymes function needs further research.
authors.affiliation: Departamento de Química/ICET, Universidade Federal de Mato Grosso (UFMT), Av. Fernando Corrêa da Costa , 2367 , Cuiaba, MT, 78060-900, Brazil. mrobioq@gmail.com.
authors.forename: Marcos Roberto
authors.initials: MR
authors.lastname: de Oliveira
authors.affiliation: Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Gustavo
authors.initials: G
authors.lastname: da Costa Ferreira
authors.affiliation: Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil.|Centro de Pesquisa da Pós-Graduação, Centro Universitário Metodista IPA, Porto Alegre, RS, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Peres
authors.affiliation: Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Simone Morelo Dal
authors.initials: SMD
authors.lastname: Bosco
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004734:Energy Metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D045784:Abietanes; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C018381:salvin
keywords: Carnosic acid; Mitochondria; Nrf2; Oxidative phosphorylation; Tricarboxylic acid cycle