Toxic Effects of Penetrating Cations

Abstract

As mitochondria are negatively charged organelles, penetrating cations are used as parts of chimeric molecules to deliver specific compounds into mitochondria. In other words, they are used as electrophilic carriers for such chemical moieties as antioxidants, dyes, etc., to transfer them inside mitochondria. However, unmodified penetrating cations affect different aspects of cellular physiology as well. In this review, we have attempted to summarise the data about the side effects of commonly used natural (e.g., berberine) and artificial (e.g., tetraphenylphosphonium, rhodamine, methylene blue) penetrating cations on cellular physiology. For instance, it was shown that such types of molecules can (1) facilitate proton transport across membranes; (2) react with redox groups of the respiratory chain; (3) induce DNA damage; (4) interfere with pleiotropic drug resistance; (5) disturb membrane integrity; and (6) inhibit enzymes. Also, the products of the biodegradation of penetrating cations can be toxic. As penetrating cations accumulate in mitochondria, their toxicity is mostly due to mitochondrial damage. Mitochondria from certain types of cancer cells appear to be especially sensitive to penetrating cations. Here, we discuss the molecular mechanisms of the toxic effects and the anti-cancer activity of penetrating cations.

Synthesis of Triphenylphosphonium-Linked Derivative of 3,5-Ditert-butyl-4-hydroxybenzylidene-malononitrile (SF6847) via Knoevenagel Reaction Yields an Effective Mitochondria-Targeted Protonophoric Uncoupler

“…On the other hand, several research groups use the term uncoupler for lipophilic TPP cations, − because they are able to effectively depolarize mitochondria in cells. Obviously, the mechanism of their action is not the selective transport of protons through lipid membranes but can be the induction of nonspecific membrane permeability similar to the detergent action on membranes in general − and mitochondria in particular. − Another possibility is connected to the presence of fatty acids in the majority of cellular membranes. According to several studies , , lipophilic TPP cations can transport protons due to the formation of complexes with fatty acids.…”

Triphenylphosphonium Analogs of Short Peptide Related to Bactenecin 7 and Oncocin 112 as Antimicrobial Agents

“…It is known that alkyl derivatives of TPP can be toxic to mammalian cells. Both antibacterial and toxic effects are observed for TPP derivatives containing a relatively long alkyl radical [ 39 , 73 ]. To test the cytotoxicity of TPP analogs 3 – 5 to mammalian cells, the Mosmann (“MTT”) assay was used [ 62 ].…”