The Drp1-CoQ10-Coa6-ETC axis represents a therapeutic target for working memory impairment caused by neuronal mitochondrial dysfunction

Coenzyme Q10 (CoQ10), the third most popular dietary supplement worldwide, shows promise in treating the ten leading non-communicable diseases linked to global mortality. However, its mechanism and potential to address memory deficits caused by cerebellar injury are not fully understood. We explored whether long-term CoQ10 supplementation could help recover working memory loss and examined the underlying mechanisms. Network pharmacology analysis identified DNM1L/Drp1 as a important genetic target of CoQ10 in cerebellar injury-related memory impairment. We generated three lines of mice with Purkinje cell (PC)-specific deficiency in Drp1 (Drp1 ^−/− mice). Multi-level assessments showed that these mice exhibited: Progressive working memory deficits (assessed via multiple behavioral tests); impaired PC plasticity (evaluated by patch-clamp recordings and morphological analysis); and disrupted mitochondrial membranes (MMs) stability and oxidative phosphorylation (OXPHOS), particularly in complexes III-V (CIII-CV) (assessed through various structural and functional assays). Long-term CoQ10 administration in drinking water for 75 days, beginning at postnatal day 15, effectively ameliorated working memory impairments (5-fold in the percentage of 45° searches), PC plasticity, and mitochondrial dysfunction in Drp1 ^−/− mice at the animal, cellular, and organelle levels. Furthermore, comprehensive drug-target fishing analyses including thermal proteome profiling (TPP), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), surface plasmon resonance (SPR), and molecular docking demonstrated that CoQ10 directly binds to cytochrome c oxidase assembly factor 6 (Coa6). This CoQ10-Coa6 interaction restored MMs stability and CIII-CV activity, revealing the Drp1-CoQ10-Coa6-electron transport chain (ETC) axis as a promising therapeutic target for memory disorders associated with neurological diseases.