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-CF 3 -phenyl TPP + moiety as an inert mitochondria-targeting carrier to safely target pharmacophores and probes to mitochondria.