Natural lipophilic inhibitors of mitochondrial complex I are candidate toxins for sporadic neurodegenerative tau pathologies

Annonacin, a natural lipophilic inhibitor of mitochondrial complex I has been implicated in the etiology of a sporadic neurodegenerative tauopathy in Guadeloupe. We therefore studied further compounds representing the broad biochemical spectrum of complex I inhibitors to which humans are potentially exposed.We determined their lipophilicity, their effect on complex I activity in submitochondrial particles, and their effect on cellular ATP levels, neuronal cell death and somatodendritic redistribution of phosphorylated tau protein (AD2 antibody against pS396/pS404-tau) in primary cultures of fetal rat striatum.The 24 compounds tested were lipophilic (logP range 0.9–8.5; exception: MPP+ logP = − 1.35) and potent complex I inhibitors (IC50 range 0.9 nM–2.6 mM). They all decreased ATP levels (EC50 range 1.9 nM–54.2 μM), induced neuronal cell death (EC50 range 1.1 nM–54.5 μM) and caused the redistribution of AD2+ tau from axons to the cell body (EC5 range 0.6 nM–33.3 μM). The potency of the compounds to inhibit complex I correlated with their potency to induce tau redistribution (r = 0.80, p < 0.001).In conclusion, we propose that the widely distributed lipophilic complex I inhibitors studied here might be implicated in the induction of tauopathies with global prevalence.