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.

• Authors: Myriam Escobar-Khondiker, Matthias Höllerhage, Marie-Paule Muriel, Pierre Champy, Antoine Bach, Christel Depienne, Gesine Respondek, Elizabeth S Yamada, Annie Lannuzel, Takao Yagi, Etienne C Hirsch, Wolfgang H Oertel, Ralf Jacob, Patrick P Michel, Merle Ruberg, Günter U Höglinger
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 27 Issue 29 Pg. 7827-37 (Jul 18 2007) ISSN: 1529-2401 [Electronic] United States
• PMID: 17634376 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Furans
• Lactones
• MAP2 protein, rat
• Microtubule-Associated Proteins
• Reactive Oxygen Species
• Tubulin Modulators
• tau Proteins
• annonacin
• Adenosine Triphosphate
• Paclitaxel

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Brain (cytology)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Embryo, Mammalian
• Enzyme Inhibitors (pharmacology)
• Female
• Furans (pharmacology)
• Lactones (pharmacology)
• Microscopy, Immunoelectron (methods)
• Microtubule-Associated Proteins (metabolism)
• Neurons (drug effects, metabolism, ultrastructure)
• Paclitaxel (pharmacology)
• Pregnancy
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Tubulin Modulators (pharmacology)
• tau Proteins (metabolism)