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 (IC(50) range 0.9 nM-2.6 mM). They all decreased ATP levels (EC(50) range 1.9 nM-54.2 microM), induced neuronal cell death (EC(50) range 1.1 nM-54.5 microM) and caused the redistribution of AD2(+) tau from axons to the cell body (EC(5) range 0.6 nM-33.3 microM). 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.
Höllerhage
Matthias
M
Experimental Neurology, Philipps Universität, Marburg, Germany.
Matusch
Andreas
A
Champy
Pierre
P
Lombès
Anne
A
Ruberg
Merle
M
Oertel
Wolfgang H
WH
Höglinger
Günter U
GU
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D024801:Tauopathies / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
D009498:Neurotoxins; D016875:tau Proteins; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I