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.