Annonacin, a Natural Mitochondrial Complex I Inhibitor, Causes Tau Pathology in Cultured Neurons

Abstract

A neurodegenerative tauopathy endemic to the Caribbean island of Guadeloupe has been associated with the consumption of anonaceous plants that contain acetogenins, potent lipophilic inhibitors of complex I of the mitochondrial respiratory chain. To test the hypothesis that annonacin, a prototypical acetogenin, contributes to the etiology of the disease, we investigated whether annonacin affects the cellular distribution of the protein tau. In primary cultures of rat striatal neurons treated for 48 h with annonacin, there was a concentration-dependent decrease in ATP levels, a redistribution of tau from the axons to the cell body, and cell death. Annonacin induced the retrograde transport of mitochondria, some of which had tau attached to their outer membrane. Taxol, a drug that displaces tau from microtubules, prevented the somatic redistribution of both mitochondria and tau but not cell death. Antioxidants, which scavenged the reactive oxygen species produced by complex I inhibition, did not affect either the redistribution of tau or cell death. Both were prevented, however, by forced expression of the NDI1 nicotinamide adenine dinucleotide (NADH)-quinone-oxidoreductase of Saccharomyces cerevisiae, which can restore NADH oxidation in complex I-deficient mammalian cells and stimulation of energy production via anaerobic glycolysis. Consistently, other ATP-depleting neurotoxins (1-methyl-4-phenylpyridinium, 3-nitropropionic, and carbonyl cyanide m-chlorophenylhydrazone) reproduced the somatic redistribution of tau, whereas toxins that did not decrease ATP levels did not cause the redistribution of tau. Therefore, the annonacin-induced ATP depletion causes the retrograde transport of mitochondria to the cell soma and induces changes in the intracellular distribution of tau in a way that shares characteristics with some neurodegenerative diseases.

Parkin maintains mitochondrial levels of the protective Parkinson’s disease-related enzyme 17-β hydroxysteroid dehydrogenase type 10

“…44,47 Standard and immunoelectron microscopy were carried out as previously described, with a JEOL 1200 EX2 electron microscope (Peabody, Peabody, MA, USA) at 80 kV (Figures 3f and g and Figure 8d). 23,60 For the localization of HSD17B10-APEX proteins, the cells were kept at room temperature for all steps from fixation to resin infiltration, and processed as previously described. 58 They were then analyzed with a Hitachi 120 kV HT 7700 transmission electron microscope (Hitachi, Tokyo, Japan) at 70 kV.…”

Atypical parkinsonism in the Caribbean island of Guadeloupe: Etiological role of the mitochondrial complex I inhibitor annonacin

“…4 We therefore investigated whether annonacin was able to induce changes in the intracellular distribution of tau. 28 To this end, we used primary cultures of striatal neurons because the striatum in addition to the midbrain was another major site of lesions in atypical parkinsonian patients 4 and in annonacin-treated rats. 26 Annonacin intoxication of striatal cultures increased tau protein levels without increasing tau mRNA levels.…”

“…Retrograde transport of mitochondria from axonal processes to cell bodies and fragmentation of microtubules were also characteristic of neuronal demise induced by annonacin. 28 Taxol, a drug used for cancer therapy that works by stabilizing microtubules, prevented the somatic redistribution of both mitochondria and tau but failed to protect against neuronal death. Antioxidants, that prevent the formation of reactive oxygen species produced during com-plex I inhibition by annonacin, 21 did not reduce the redistribution of tau, and afforded no protection against cell death.…”

Axonal Transport and Mitochondrial Dysfunction in Alzheimer's Disease

“…Tau hyperphosphorylation and aggregation can also result, for example, from inhibition of mitochondrial respiratory chain complex I [91]. On the other hand, heterologous expression of human tau in Drosophila larval motor neurons causes functional changes of neuromuscular junctions, including decreased evoked synaptic potentials [92].…”