Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks
Sofia Benfeito, Carlos Fernandes, Daniel Chavarria, Sandra Barreiro, Fernando Cagide, Lisa Sequeira, José Teixeira, Renata Silva, Fernando Remião, Paulo J. Oliveira, Eugenio Uriarte, Fernanda Borges
Abstract
Although the lipophilic triphenylphosphonium (TPP + ) cation is widely used to target antioxidants to mitochondria, TPP + -based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2) cells, decreasing intracellular adenosine triphosphate (ATP) levels, leading to mitochondrial membrane depolarization and reduced mitochondrial mass after 24 h. We surpassed this concern using nitrogen-derived cationic carriers ( Mito.PICO, Mito.ISOQ, and Mito.IMIDZ ). As opposed to Mito.TPP, these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells up to 50 μM and after 24 h of incubation. All of the cationic derivatives accumulated inside the mitochondrial matrix and acted as neuroprotective agents against iron(III), hydrogen peroxide, and tert -butyl hydroperoxide insults. The overall data showed that nitrogen-based cationic carriers can modulate the biological performance of mitochondria-directed antioxidants and are an alternative to the TPP cation.