Lipophilic Cations as Mitochondria-Targeting Moieties: Recent Progress and Design Principles for Medicinal Chemistry

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).