Reversing Signs of Parkinsonism in a Cell Model Using Mitochondria-Targeted Organoiridium Catalysis

We report the application of organoiridium complexes
as catalytic
agents for the detoxification of biogenic reactive aldehyde species
(RASP), which are implicated in the pathogenesis of neurodegenerative
disorders. We show that Ir complexes functionalized with phosphonium
cations localize selectively in the mitochondria and have better cellular
retention compared to that of their parent Ir species. In a cell model
for Parkinsonism, the mitochondria-targeted iridium catalysts exhibited
superior cell protecting abilities and longer-lasting effects (up
to 6 d) than conventional RASP scavengers, which failed to be effective
beyond 24 h. Our biological assays indicate that treatment with the
Ir compounds led to reduction in reactive oxygen species and aldehyde
levels while partially preserving the native mitochondrial membrane
potential and NAD+/NADH ratio in 1-methyl-4-phenylpyridinium-inhibited
cells. Our work is the first to demonstrate catalytic nonenzymatic
detoxification of RASP in living systems.