Mitochondrial respiratory complex I can be inhibited via bypassing the ubiquinone‐accessing tunnel

Mitochondrial NADH–ubiquinone oxidoreductase (complex I) couples electron transfer from NADH to ubiquinone with proton translocation in its membrane part. Structural studies have identified a long (~ 30 Å), narrow, tunnel‐like cavity within the enzyme, through which ubiquinone may access a deep reaction site. Although various inhibitors are considered to block the ubiquinone reduction by occupying the tunnel's interior, this view is still debatable. We synthesized a phosphatidylcholine‐quinazoline hybrid compound (PC‐Qz1), in which a quinazoline‐type toxophore was attached to the sn‐2 acyl chain to prevent it from entering the tunnel. However, PC‐Qz1 inhibited complex I and suppressed photoaffinity labeling by another quinazoline derivative, [125I]AzQ. This study provides further experimental evidence that is difficult to reconcile with the canonical ubiquinone‐accessing tunnel model. Respiratory complex I couples electron transfer with proton translocation, involving a debated tunnel‐like cavity for ubiquinone access. We synthesized a phosphatidylcholine‐quinazoline hybrid inhibitor (PC‐Qz1) to prevent it from entering the tunnel. However, PC‐Qz1 inhibited complex I and suppressed labeling by photoreactive quinazoline derivative. This study provides further experimental evidence that is difficult to reconcile with the canonical ubiquinone‐accessing tunnel model.