Assessing mitochondria-targeted acyl hydroquinones on the mitochondrial platelet function and cytotoxic activity: Role of the linker length

• Published in: Free radical biology & medicine 2023-11, Vol.208, p.26-36
• Main Authors: Montecino-Garrido, Héctor, Sepúlveda, Magdalena, Méndez, Diego, Monroy-Cárdenas, Matías, Alfaro, Sergio, González-Avendaño, Mariela, Caballero, Julio, Urra, Félix A., Araya-Maturana, Ramiro, Fuentes, Eduardo
• Format: Article
• Language: English
• Subjects: Antiplatelet; Bioenergetics; Bioinformatics; Hydroquinone derivatives; Mitochondrial-targeted drug; Triphenylphosphonium; Viability
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.07.030

The use of triphenylphosphonium cation (TPP+) linked to phenolic compounds by alkyl chains has a significant relevance as a mitochondrial delivery strategy in biomedicine because it affects mitochondrial bioenergetics in models of noncommunicable diseases such as cancer and cardiovascular-related conditions. Studies indicate that a long alkyl chain (10–12 carbon) increases the mitochondrial accumulation of TPP+-linked drugs. In contrast, other studies show that these compounds are consistently toxic to micromolar concentrations (as observed in platelets). In the present study, we evaluated the in vitro effect of three series of triphenylphosphonium-linked acyl hydroquinones derivates on the metabolism and function of human platelets using 3–9 carbons for the alkyl linker. Those were assessed to determine the role of the length of the alkyl chain linker on platelet toxicity. Human platelets were exposed in vitro to different concentrations (2–40 μM) of every compound; cellular viability, phosphatidylserine exposition, mitochondrial membrane potential (ΔΨm), intracellular calcium release, and intracellular ROS generation were assessed by flow cytometry. An in silico energetic profile was generated with Umbrella sampling molecular dynamics (MD). There was an increase in cytotoxic activity directly related to the length of the acyl chain and lipophilicity, as seen by three techniques, and this was consistent with a decrease in ΔΨm. The in silico energetic profiles point out that the permeability of the mitochondrial membrane may be involved in the cytotoxicity of phosphonium salts. This information may be relevant for the design of new TPP+ -based drugs with a safe cardiovascular profile. [Display omitted] •The toxicity of TPP + -linked compounds on platelets correlates with the chain length and lipophilicity.•Mitochondrial membrane may be involved in the cytotoxicity of phosphonium salts.•Mitochondrial-targeted acylhydroquinones can be considered for promising anti-thrombotic treatments.