A Novel Triphenylphosphonium Carrier to Target Mitochondria without Uncoupling Oxidative Phosphorylation

Mitochondrial dysfunction is an underlying pathology in numerous diseases. Delivery of diagnostic and therapeutic cargo directly into mitochondria is a powerful approach to study and treat these diseases. The triphenylphosphonium (TPP⁺) moiety is the most widely used mitochondriotropic carrier. However, studies have shown that TPP⁺ is not inert; TPP⁺ conjugates uncouple mitochondrial Oxidative Phosphorylation. To date, all efforts toward addressing this problem have focused on modifying lipophilicity of TPP⁺-linker-cargo conjugates to alter mitochondrial uptake, albeit with limited success. We show that structural modifications to the TPP⁺ phenyl rings that decrease electron density on the phosphorus atom can abrogate uncoupling activity as compared to the parent TPP⁺ moiety and prevent dissipation of mitochondrial membrane potential. These alterations of the TPP⁺ structure do not negatively affect the delivery of cargo to mitochondria. Results here identify the 4-CF₃-phenyl TPP⁺ moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.