Fig. 2

Aripiprazole, Brexpiprazole, and Cariprazine directly inhibit respiratory complex I via the Q-channel. A Normalised basal and maximal OCR measurements from SH-SY5Y cells treated for 4 h with indicated concentrations of aripiprazole, dehydroaripiprazole, brexpiprazole, cariprazine or didesmethylcariprazine (mean ± SEM from 4 independent experiments, asterisks, one-way ANOVA with Dunnett’s multiple comparison test, normalised to control) (corresponds to Additional file 1: Fig. S3C). B Normalised OCR measurements driven by complex I substrates (pyruvate/malate) or the complex II substrate (succinate). Permeabilised SH-SY5Y cells were treated with 10 μM aripiprazole, dehydroaripiprazole, brexpiprazole, cariprazine or 5 μM piericidin A, antimycin A (mean ± SEM from 4 independent experiments, asterisks, one-way ANOVA with Dunnett’s multiple comparison test, normalised to control) (corresponds to Additional file 1: Fig. S4B). C A cartoon depiction of mammalian complex I structure with the two substrate-binding sites indicated. D Normalised NADH:O₂ oxidoreduction rates of bovine mitochondrial membranes exposed to varying concentrations of aripiprazole, brexpiprazole, cariprazine, dehydroaripiprazole and didesmethylcariprazine. Respective IC₅₀ values from the standard dose–effect relationship (see “Methods” Section) are indicated in brackets. E Normalised NADH:APAD⁺, F NADH:FeCN, and G NADH:DQ oxidoreduction rates of isolated bovine complex I exposed to 100 μM aripiprazole, brexpiprazole, cariprazine or 1 µM piericidin A (mean ± SEM from 3 independent wells per treatment, asterisks, one-way ANOVA with Dunnett’s multiple comparison test, normalised to control)