title: Dysfunction of mitochondrial Lon protease and identification of oxidized protein in mouse brain following exposure to MPTP: Implications for Parkinson disease.
abstract: Compelling evidence suggests that mitochondrial dysfunction leading to reactive oxygen species (ROS) production and protein oxidation could represent a critical event in the pathogenesis of Parkinson's disease (PD). Pioneering studies have shown that the mitochondrial matrix contains the Lon protease, which degrades oxidized, dysfunctional, and misfolded protein. Using the PD animal model of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxication in mice, we showed that Lon protease expression increased in the ventral mesencephalon of intoxicated animals, concomitantly with the appearance of oxidized proteins and dopaminergic cell loss. In addition, we report that Lon is inactivated by ROS. Moreover, proteomic experiments provide evidence of carbonylation in α-ketoglutarate dehydrogenase (KGDH), aconitase or subunits of respiratory chain complexes. Lon protease inactivation upon MPTP treatment in mice raises the possibility that Lon protease dysfunction is an early event in the pathogenesis of PD.
authors.affiliation: INSERM, U1127, The Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France; CNRS, UMR 7225, Centre de Recherche en neurosciences, ICM, Thérapeutique expérimentale de la neurodégénérescence, Hôpital de la Salpêtrière, Paris, F-75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France. Electronic address: anne-laure.bulteau@ens-lyon.fr.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bulteau
authors.affiliation: INSERM, U1127, The Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France; CNRS, UMR 7225, Centre de Recherche en neurosciences, ICM, Thérapeutique expérimentale de la neurodégénérescence, Hôpital de la Salpêtrière, Paris, F-75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France; Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile; Millennium Institute of Cell Dynamics and Biotechnology, Santiago, Chile.
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Mena
authors.affiliation: Laboratoire Mitochondries, Métaux et Stress Oxydatif, Département de Pathologie Moléculaire et Cellulaire, Institut Jacques Monod, Université Paris-Diderot/CNRS, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Auchère
authors.affiliation: Case Western Reserve University Department of Chemistry, Cleveland, OH 44106, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Lee
authors.affiliation: INSERM, U1127, The Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France; CNRS, UMR 7225, Centre de Recherche en neurosciences, ICM, Thérapeutique expérimentale de la neurodégénérescence, Hôpital de la Salpêtrière, Paris, F-75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Prigent
authors.affiliation: INSERM, U1127, The Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France; CNRS, UMR 7225, Centre de Recherche en neurosciences, ICM, Thérapeutique expérimentale de la neurodégénérescence, Hôpital de la Salpêtrière, Paris, F-75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Lobsiger
authors.affiliation: Laboratoire Mitochondries, Métaux et Stress Oxydatif, Département de Pathologie Moléculaire et Cellulaire, Institut Jacques Monod, Université Paris-Diderot/CNRS, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Camadro
authors.affiliation: INSERM, U1127, The Brain and Spinal Cord Institute (ICM), Hôpital de la Salpêtrière, 75013 Paris, France; CNRS, UMR 7225, Centre de Recherche en neurosciences, ICM, Thérapeutique expérimentale de la neurodégénérescence, Hôpital de la Salpêtrière, Paris, F-75005 Paris, France; Sorbonne Universités, Université Pierre et Marie Curie, 75005 Paris, France. Electronic address: etienne.hirsch@upmc.fr.
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000378:metabolism*; D049070:Protease La / Q000378:metabolism*; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D045222:Electron Transport Chain Complex Proteins; D017382:Reactive Oxygen Species; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007655:Ketoglutarate Dehydrogenase Complex; D049070:Protease La; D000154:Aconitate Hydratase
keywords: Lon protease; Mitochondria; Oxidative stress; Parkinson's disease; Protein oxidation