Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson's disease model

• Published in: The Journal of cell biology Vol. 192; no. 5; pp. 873 - 882
• Main Authors: Choi, Won-Seok, Palmiter, Richard D, Xia, Zhengui
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 07.03.2011; Rockefeller University Press
• Subjects: 1-Methyl-4-phenylpyridinium - pharmacology; Animals; Cytoplasm - drug effects; Cytoplasm - metabolism; Disease Models, Animal; Dopamine - metabolism; Electron Transport Complex I - antagonists & inhibitors; Electron Transport Complex I - drug effects; Electron Transport Complex I - genetics; Electron Transport Complex I - physiology; Medical treatment; Mice; Microtubules - drug effects; Microtubules - physiology; NAD - metabolism; NAD - physiology; Nerve Degeneration - etiology; Neurons; Pareto optimum; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Reactive Oxygen Species - metabolism; Risk factors; Rodents; Rotenone - pharmacology; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Substantia Nigra - pathology; Toxicity; Vesicular Monoamine Transport Proteins - antagonists & inhibitors
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201009132

Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson's disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4⁺/⁺ or Ndufs4⁻/⁻ mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson's disease.