Lipophilic cations as mitochondria-targeting moieties : recent progress and design principles for medicinal chemistry

Džajić, Ivan (author), Tomašič, Tihomir (author), Pardo A., Luis (author), Peterlin-Mašič, Lucija (author), Cotman, Andrej Emanuel (author)

Mitochondria-targeting technology, in the form of (lipophilic cation)–(small molecule) conjugates, was first discussed more than 50 years ago. Since then, the triphenylphosphonium (TPP) cation has become synonymous with the concept of a mitochondria-targeting moiety (MTM). The discovery of its ability to accumulate in mitochondria occurred alongside research on mitochondrial functions and the mechanisms underlying cation import. The recognition of intrinsic biological effects of TPP, apart from delivery of functional cargo, came much later, prompting the development of novel MTMs beyond the archetypal TPP. In this Perspective, we present the current understanding of the biological mechanisms of action of mitochondria-targeting conjugates, describe the methods used for their validation, and overview the recently developed novel mitochondria-targeting moieties. Building upon the recent advances, we propose a rational approach for the development of novel MTMs to be incorporated into the future MTM–linker–cargo therapeutics (MITACs, MITochondria-TArgeting Conjugates).

• Language: English
• Keywords: assays, cations, conjugate acid-base pairs, mitochondria, sensor probes
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 23690−23704
• Numbering: Vol. 68, iss. 22
• PID: 20.500.12556/RUL-177231
• UDC: 543.2/.9
• ISSN on article: 1520-4804
• DOI: 10.1021/acs.jmedchem.5c02076
• COBISS.SI-ID: 261779971
• Publication date in RUL: 18.12.2025

Record is a part of a journal

• Title: Journal of medicinal chemistry
• Shortened title: J. med. chem.
• Publisher: American Chemical Society
• ISSN: 1520-4804
• COBISS.SI-ID: 512806681

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: analize, kationi, konjugirani kislinsko-bazni par, mitohondriji, senzorske sonde, farmacevtska kemija, klinična kemija