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

Abstract

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.