Mitochondriotropics: A review of their mode of action, and their applications for drug and DNA delivery to mammalian mitochondria

Since compounds targeting mitochondria exhibit diverse accumulation mechanisms and chemical features, various questions arise. Do such “mitochondriotropics” have a characteristic chemistry? What are mitochondrial uptake mechanisms? Do mitochondriotropics necessarily accumulate in mitochondria or merely have access? Is the concept “mitochondriotropic” of any practical value? To seek answers, a non-biased sample of > 100 mitochondriotropics was generated from the review literature. This dataset was examined using: physicochemical classification; quantitative structure-activity relations (QSAR) models; and a Fick–Nernst–Planck physicochemical model. The ability of the latter two approaches to predict mitochondriotropic behaviour was assessed, and comparisons made between methods, and with current assumptions. All approaches provided instructive pictures of the nature of mitochondriotropics. Thus although lipophilic cations are regarded as the commonest structural type, only a third were such. Much the same proportion were acids, potentially or actually anions. Many mitochondriotropics were electrically neutral compounds. All categorizations involved overall molecular properties, not the presence of “mitochondriotropic tags” — again contrary to literature concepts. Selective mitochondrial accumulation involved electric potential, ion-trapping, and complex formation with cardiolipin; non-specific accumulation involved membrane partitioning. Non-specific access required only low lipophilicity. Mitochondrial targeting did not preclude additional accumulation sites, e.g. lysosomes. The concept “mitochondriotropic” remains useful, although may imply access, not accumulation. QSAR and Fick–Nernst–Planck approaches are complementary — neither is universally applicable. Using both approaches enabled the mitochondriotropic behavior of > 80% of the dataset to be predicted, and the physicochemistry of mitochondriotropics to be specified in some detail. This can facilitate guided syntheses and selection of optimal mitochondriotropic structures.