TY - JOUR
T1 - Cytotoxicity and mitochondrial effects of phenolic and quinone‐based mitochondria‐targeted and untargeted antioxidants on human neuronal and hepatic cell lines
T2 - a comparative analysis
AU - Fernandes, Carlos
AU - Videira, Afonso J. C.
AU - Veloso, Caroline D.
AU - Benfeito, Sofia
AU - Soares, Pedro
AU - Martins, João D.
AU - Gonçalves, Beatriz
AU - Duarte, José F. S.
AU - Santos, António M.S.
AU - Oliveira, Paulo J.
AU - Borges, Fernanda
AU - Teixeira, José
AU - Silva, Filomena S. G.
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/11
Y1 - 2021/11
N2 - Mitochondriotropic antioxidants (MC3, MC6.2, MC4 and MC7.2) based on dietary antioxidants and analogs (caffeic, hydrocaffeic, trihydroxyphenylpropanoic and trihydroxycinnamic acids) were developed. In this study, we evaluate and compare the cytotoxicity profile of novel mitochondria‐targeted molecules (generally known as MitoCINs) on human HepG2 and differentiated SH‐SY5Y cells with the quinone‐based mitochondria‐targeted antioxidants MitoQ and SkQ1 and with two non‐targeted antioxidants, resveratrol and coenzyme Q10 (CoQ10). We further evaluate their effects on mitochondrial membrane potential, cellular oxygen consumption and extracellular acidification rates. Overall, MitoCINs derivatives reduced cell viability at concentrations about six times higher than those observed with MitoQ and SkQ1. A toxicity ranking for both cell lines was produced: MC4 < MC7.2 < MC3 < MC6.2. These results suggest that C‐6 carbon linker and the presence of a pyrogallol group result in lower cytotoxicity. MC3 and MC6.2 affected the mitochondrial function more significantly relative to MitoQ, SkQ1, resveratrol and CoQ10, while MC4 and MC7.2 displayed around 100–1000× less cytotoxicity than SkQ1 and MitoQ. Based on the mitochondrial and cytotoxicity cellular data, MC4 and MC7.2 are proposed as leads that can be optimized to develop safe drug candidates with therapeutic application in mitochondrial oxidative stress‐related diseases.
AB - Mitochondriotropic antioxidants (MC3, MC6.2, MC4 and MC7.2) based on dietary antioxidants and analogs (caffeic, hydrocaffeic, trihydroxyphenylpropanoic and trihydroxycinnamic acids) were developed. In this study, we evaluate and compare the cytotoxicity profile of novel mitochondria‐targeted molecules (generally known as MitoCINs) on human HepG2 and differentiated SH‐SY5Y cells with the quinone‐based mitochondria‐targeted antioxidants MitoQ and SkQ1 and with two non‐targeted antioxidants, resveratrol and coenzyme Q10 (CoQ10). We further evaluate their effects on mitochondrial membrane potential, cellular oxygen consumption and extracellular acidification rates. Overall, MitoCINs derivatives reduced cell viability at concentrations about six times higher than those observed with MitoQ and SkQ1. A toxicity ranking for both cell lines was produced: MC4 < MC7.2 < MC3 < MC6.2. These results suggest that C‐6 carbon linker and the presence of a pyrogallol group result in lower cytotoxicity. MC3 and MC6.2 affected the mitochondrial function more significantly relative to MitoQ, SkQ1, resveratrol and CoQ10, while MC4 and MC7.2 displayed around 100–1000× less cytotoxicity than SkQ1 and MitoQ. Based on the mitochondrial and cytotoxicity cellular data, MC4 and MC7.2 are proposed as leads that can be optimized to develop safe drug candidates with therapeutic application in mitochondrial oxidative stress‐related diseases.
KW - Phenolic‐based mitochondriotropic antioxidants
KW - Quinone‐based mitochondriotropic antioxidants
KW - Non‐targeted antioxidants
UR - https://www.scopus.com/pages/publications/85118164047
U2 - 10.3390/biom11111605
DO - 10.3390/biom11111605
M3 - Article
C2 - 34827603
AN - SCOPUS:85118164047
SN - 2218-273X
VL - 11
JO - Biomolecules
JF - Biomolecules
IS - 11
M1 - 1605
ER -