title: The Hsp60 folding machinery is crucial for manganese superoxide dismutase folding and function.
abstract: Even though the deleterious effects of increased reactive oxygen species (ROS) levels have been implicated in a variety of neurodegenerative disorders, the triggering events that lead to the increased ROS and successive damages are still ill-defined. Mitochondria are the key organelles controlling the ROS balance, being their main source and also counteracting them by the action of the ROS scavenging system. Mitochondria, moreover, control the presence of ROS-damaged proteins by action of the protein quality control (PQC) system. One of its components is the mitochondrial chaperone Hsp60 assisting the folding of a subset of mitochondrial matrix proteins. Mutations in Hsp60 cause a late onset form of the neurodegenerative disease hereditary spastic paraplegia (SPG13). In this study, we aimed to address the molecular consequences of Hsp60 shortage. We here demonstrate that a heterozygous knockout Hsp60 model that recapitulates features of the human disease and exhibits increased oxidative stress in neuronal tissues. Moreover, we indicate that the increase of ROS is, at least in part, due to impaired folding of the manganese superoxide dismutase (MnSOD), a key antioxidant enzyme. We observed that the Hsp60 and MnSOD proteins interact. Based on these results, we propose that MnSOD is a substrate of the Hsp60 folding machinery and that under conditions of diminished availability of Hsp60, MnSOD is impaired in reaching the native state. This suggests a possible link between Hsp60-dependent PQC and the ROS scavenging systems that may have the function to increase ROS production under conditions of folding stress.
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Aarhus University , Aarhus , Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Magnoni
authors.forename: J
authors.initials: J
authors.lastname: Palmfeldt
authors.forename: J
authors.initials: J
authors.lastname: Hansen
authors.forename: J H
authors.initials: JH
authors.lastname: Christensen
authors.forename: T J
authors.initials: TJ
authors.lastname: Corydon
authors.forename: P
authors.initials: P
authors.lastname: Bross
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology; D018834:Chaperonin 60 / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000502:physiology*; D018384:Oxidative Stress; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000099156:Superoxide Dismutase 2
chemical_list: D018834:Chaperonin 60; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C557066:Hspd1 protein, mouse