TY - JOUR
T1 - Targeting hydroxybenzoic acids to mitochondria as a strategy to delay skin ageing
T2 - an in vitro approach
AU - Fernandes, Carlos
AU - Cagide, Fernando
AU - Simões, Jorge
AU - Pita, Carlos
AU - Pereira, Eurico
AU - Videira, Afonso J. C.
AU - Soares, Pedro
AU - Duarte, José F.S.
AU - Santos, António M.S.
AU - Oliveira, Paulo J.
AU - Borges, Fernanda
AU - Silva, Filomena S.G.
N1 - Funding Information:
This article has been developed in the framework of “38429 TAG2020: Investigação de antioxidantes inovadores para introdução em cosmética e saúde animal” by MITOTAG, LDA. Project supported by CENTRO 2020 of PT2020 through the European Regional Development Fund (ERDF) and Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UIDB/00081/2020 (CIQUP) and LA/P/0056/2020 (IMS). FC thanks FCT, POPH and FEDER/COMPETE for its contract.
Publisher Copyright:
© 2022 by the authors.
PY - 2022/10
Y1 - 2022/10
N2 - Targeting antioxidants to mitochondria is considered a promising strategy to prevent cellular senescence and skin ageing. In this study, we investigate whether four hydroxybenzoic acid-based mitochondria-targeted antioxidants (MitoBENs, MB1-4) could be used as potential active ingredients to prevent senescence in skin cells. Firstly, we evaluated the chemical stability, cytotoxicity, genotoxicity and mitochondrial toxicity of all compounds. We followed this by testing the antioxidant protective capacity of the two less toxic compounds on human skin fibroblasts. We then assessed the effects of the best hit on senescence, inflammation and mitochondrial remodeling on a 3D skin cell model, while also testing its mutagenic potential. Cytotoxicity and mitochondrial toxicity rankings were produced: MB3 < MB4 ≃ MB1 < MB2 and MB3 < MB1 < MB4 < MB2, respectively. These results suggest that pyrogallol-based compounds (MB2 and MB4) have lower cytotoxicity. The pyrogallol derivative, MB2, containing a 6-carbon spacer, showed a more potent antioxidant protective activity against hydrogen peroxide cytotoxicity. In a 3D skin cell model, MB2 also decreased transcripts related to senescence. In sum, MB2’s biological safety profile, good chemical stability and lack of mutagenicity, combined with its anti-senescence effect, converts MB2 into a good candidate for further development as an active ingredient for skin anti-ageing products.
AB - Targeting antioxidants to mitochondria is considered a promising strategy to prevent cellular senescence and skin ageing. In this study, we investigate whether four hydroxybenzoic acid-based mitochondria-targeted antioxidants (MitoBENs, MB1-4) could be used as potential active ingredients to prevent senescence in skin cells. Firstly, we evaluated the chemical stability, cytotoxicity, genotoxicity and mitochondrial toxicity of all compounds. We followed this by testing the antioxidant protective capacity of the two less toxic compounds on human skin fibroblasts. We then assessed the effects of the best hit on senescence, inflammation and mitochondrial remodeling on a 3D skin cell model, while also testing its mutagenic potential. Cytotoxicity and mitochondrial toxicity rankings were produced: MB3 < MB4 ≃ MB1 < MB2 and MB3 < MB1 < MB4 < MB2, respectively. These results suggest that pyrogallol-based compounds (MB2 and MB4) have lower cytotoxicity. The pyrogallol derivative, MB2, containing a 6-carbon spacer, showed a more potent antioxidant protective activity against hydrogen peroxide cytotoxicity. In a 3D skin cell model, MB2 also decreased transcripts related to senescence. In sum, MB2’s biological safety profile, good chemical stability and lack of mutagenicity, combined with its anti-senescence effect, converts MB2 into a good candidate for further development as an active ingredient for skin anti-ageing products.
KW - Hydroxybenzoic acid-based mitochondria-targeted antioxidants
KW - Mitochondria
KW - Oxidative stress
KW - Senescence
KW - Skin ageing
UR - http://www.scopus.com/inward/record.url?scp=85139863433&partnerID=8YFLogxK
U2 - 10.3390/molecules27196183
DO - 10.3390/molecules27196183
M3 - Article
C2 - 36234718
AN - SCOPUS:85139863433
SN - 1420-3049
VL - 27
JO - Molecules
JF - Molecules
IS - 19
M1 - 6183
ER -