Selective and reversible disruption of mitochondrial inner membrane protein complexes by lipophilic cations.

• Mitochondrially targeted compounds using the triphenylphosphonium (TPP+) moiety are widely used for research and therapeutic purposes. • Previous studies have shown significant functional effects of the targeting moiety itself, without any targeted substance. • This study significantly extends the knowledge about these effects on mitochondrial membrane protein levels and tests several hypotheses about the mechanism. • Triphenylphosphonium-based lipophilic cations exert profound but reversible effects on a mitochondrial ETC proteins, which cannot be explained only by a loss of membrane potential. Triphenylphosphonium (TPP) derivatives are commonly used to target chemical into mitochondria. We show that alkyl-TPP cause reversible, dose- and hydrophobicity-dependent alterations of mitochondrial morphology and function and a selective decrease of mitochondrial inner membrane proteins including subunits of the respiratory chain complexes, as well as components of the mitochondrial calcium uniporter complex. The treatment with alkyl-TPP resulted in the cleavage of the pro-fusion and cristae organisation regulator Optic atrophy-1. The structural and functional effects of alkyl-TPP were found to be reversible and not merely due to loss of membrane potential. A similar effect was observed with the mitochondria-targeted antioxidant MitoQ. [ABSTRACT FROM AUTHOR]