Cytotoxicity and Mitochondrial Effects of Phenolic and Quinone-Based Mitochondria-Targeted and Untargeted Antioxidants on Human Neuronal and Hepatic Cell Lines: A Comparative Analysis
Carlos Fernandes,
Afonso J. C. Videira,
Caroline D. Veloso,
Sofia Benfeito,
Pedro Soares,
João D. Martins,
Beatriz Gonçalves,
José F. S. Duarte,
António M. S. Santos,
Paulo J. Oliveira,
Fernanda Borges,
José Teixeira,
Filomena S. G. Silva
Affiliations
Carlos Fernandes
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
Afonso J. C. Videira
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
Caroline D. Veloso
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
Sofia Benfeito
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
Pedro Soares
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
João D. Martins
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
Beatriz Gonçalves
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
José F. S. Duarte
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
António M. S. Santos
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
Paulo J. Oliveira
CNC—Center for Neuroscience and Cell Biology, CIBB—Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal
Fernanda Borges
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
José Teixeira
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
Filomena S. G. Silva
Mitotag, Biocant Park, Parque Tecnológico de Cantanhede, Núcleo 04, Lote 4, 3060-197 Cantanhede, Portugal
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 7.2 3 6.2. 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 times 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.
