Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks

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.

Effects of Dityrosine on Lactic Acid Metabolism in Mice Gastrocnemius Muscle During Endurance Exercise via the Oxidative Stress-Induced Mitochondria Damage

“…In this study, we observed mitochondrial membrane depolarization in the gastrocnemius of Dityr-treated mice, which suggested that the integrity of the mitochondrial membrane structure was damaged by Dityr. Numerous studies have affirmed the connection between membrane depolarization and ATP generation . When coupled with the preceding experimental outcomes, it is substantiated that Dityr exposure may induce mitochondrial dysfunction.…”

“…Numerous studies have affirmed the connection between membrane depolarization and ATP generation. 51 When coupled with the preceding experimental outcomes, it is substantiated that Dityr exposure may induce mitochondrial dysfunction. Furthermore, the current investigation has demonstrated the detrimental impact of Dityr treatment on various pivotal processes implicated in the regulation of mitochondrial function within the gastrocnemius muscle of mice.…”

Efficacy of Novel Quaternary Ammonium and Phosphonium Salts Differing in Cation Type and Alkyl Chain Length against Antibiotic-Resistant Staphylococcus aureus

“…The data revealed that only compound 2e exhibited no detrimental effects on cellular health, as indicated by a 90.88% NR uptake. This highlights the significance of replacing the TPP cation with alternative nitrogen-based carriers to reduce inherent toxicity [ 79 ].…”

Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives

“…The chromatographic hydrophobicity index (CHI) values at pH 2.3 were determined using an experimental protocol described elsewhere . The acidic conditions used were relevant to prevent ionization of the phenolic function and to avoid peak tailing.…”

“…The chromatographic hydrophobicity index (CHI) values at pH 2.3 were determined using an experimental protocol described elsewhere. 12 The acidic conditions used were relevant to prevent ionization of the phenolic function and Statistical Analysis. For each assay, all experiments were performed in triplicate and the coefficient of variation was always <10%.…”