Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP⁺, or paraquat

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 39; pp. 15136 - 15141
• Main Authors: Choi, Won-Seok, Kruse, Shane E, Palmiter, Richard D, Xia, Zhengui
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 30.09.2008; National Acad Sciences
• Subjects: Animals; Apoptosis; Biological Sciences; Cell culture; Cell death; Cultured cells; Dopamine - metabolism; Dopaminergic neurons; Gene Deletion; Genes; Mice; Mice, Mutant Strains; Mitochondria; NADH Dehydrogenase - antagonists & inhibitors; NADH Dehydrogenase - genetics; NADH Dehydrogenase - metabolism; Neurons; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Neuroscience; Oxygen consumption; Paraquat - toxicity; Parkinson disease; Parkinson Disease - enzymology; Parkinson Disease - pathology; Parkinson's disease; Proteins; Respiration; Rodents; Rotenone - toxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0807581105

Inhibition of mitochondrial complex I is one of the leading hypotheses for dopaminergic neuron death associated with Parkinson's disease (PD). To test this hypothesis genetically, we used a mouse strain lacking functional Ndufs4, a gene encoding a subunit required for complete assembly and function of complex I. Deletion of the Ndufs4 gene abolished complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice, but did not affect the survival of dopaminergic neurons in culture. Although dopaminergic neurons were more sensitive than other neurons in these cultures to cell death induced by rotenone, MPP⁺, or paraquat treatments, the absence of complex I activity did not protect the dopaminergic neurons, as would be expected if these compounds act by inhibiting complex 1. In fact, the dopaminergic neurons were more sensitive to rotenone. These data suggest that dopaminergic neuron death induced by treatment with rotenone, MPP⁺, or paraquat is independent of complex I inhibition.