title: Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo.
abstract: Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson's disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.
authors.affiliation: Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; College of Life Sciences, Sejong University, Seoul, Korea.
authors.forename: Hyung-Wook
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju, Korea.
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Choi
authors.affiliation: Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Sorscher
authors.affiliation: School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, Korea; College of Medicine, Chonnam National University, Gwangju, Korea.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie, UMR_CR18, Neuroscience Paris-Seine, Paris, France; Centre National de la Recherche Scientifique UMR 8246, Paris, France; Institut National de la Santé et de la Rechesrche Médicale U1130, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.affiliation: Howard Huges Medical Institute, University of Washington, Seattle, WA, USA; Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.affiliation: Toxicology Program in the Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA; Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, WA, USA. Electronic address: zxia@uw.edu.
authors.forename: Zhengui
authors.initials: Z
authors.lastname: Xia
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; C534449:Ndufs4 protein, mouse; C440529:UBC antigen; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D042967:Electron Transport Complex I; D004298:Dopamine
keywords: Dopamine neuron; Mitochondrial complex I; Parkinson's disease