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.