β-Carbolines increase the performance of the respiratory chain in mitochondria

Abstract

The neurotoxin MPP+ was infused into the left lateral ventricle of rat brain for 4 weeks followed by infusion of saline and 9-methyl-βC, respectively, for 2 weeks. A dose of MPP+ was selected which reduced the level of dopamine (DA) in the striatum by approximately 50% at the end of the 6-week infusion period with MPP+/saline. This condition should correspond to an early stage of Parkinson's disease. The mitochondrial proteome was investigated with emphasis on the composition, abundance, structure, and activity of membrane proteins and supercomplexes. We did not find changes in the catalytic activity of supercomplexes containing complex I in striatal homogenates from rats treated with MPP+/saline. The in-gel measurement of the nicotinamide adenine dinucleotide dehydrogenase activity revealed that 9-methyl-βC stimulated the enzyme activity of complex I in rats pretreated with MPP+ (+80%). This increase was primarily caused by a specific supercomplex (I1III2IV2), which was approximately three times more active in MPP+/9-methyl-βC than in MPP+/saline treated rats. The abundance of complex IV was not different among groups. These findings suggest that 9-methyl-βC specifically interacts with the dimer of complex IV in supercomplex I1III2IV2 The improvement of the perfor¬mance of the respiratory chain probably contributed to the observed restorative effects of the βC by providing more ATP and by protecting mitochondria from the deleterious action of toxic oxygen species by reducing their production.