title: RCAN1 regulates mitochondrial function and increases susceptibility to oxidative stress in mammalian cells.
abstract: Mitochondria are the primary site of cellular energy generation and reactive oxygen species (ROS) accumulation. Elevated ROS levels are detrimental to normal cell function and have been linked to the pathogenesis of neurodegenerative disorders such as Down's syndrome (DS) and Alzheimer's disease (AD). RCAN1 is abundantly expressed in the brain and overexpressed in brain of DS and AD patients. Data from nonmammalian species indicates that increased RCAN1 expression results in altered mitochondrial function and that RCAN1 may itself regulate neuronal ROS production. In this study, we have utilized mice overexpressing RCAN1 (RCAN1(ox)) and demonstrate an increased susceptibility of neurons from these mice to oxidative stress. Mitochondria from these mice are more numerous and smaller, indicative of mitochondrial dysfunction, and mitochondrial membrane potential is altered under conditions of oxidative stress. We also generated a PC12 cell line overexpressing RCAN1 (PC12(RCAN1)). Similar to RCAN1(ox) neurons, PC12(RCAN1) cells have an increased susceptibility to oxidative stress and produce more mitochondrial ROS. This study demonstrates that increasing RCAN1 expression alters mitochondrial function and increases the susceptibility of neurons to oxidative stress in mammalian cells. These findings further contribute to our understanding of RCAN1 and its potential role in the pathogenesis of neurodegenerative disorders such as AD and DS.
authors.affiliation: Molecular and Cellular Neuroscience Group, Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Heshan
authors.initials: H
authors.lastname: Peiris
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Daphne
authors.initials: D
authors.lastname: Dubach
authors.affiliation: Islet Biology Laboratory, Department of Anatomy and Histology and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia ; Discipline of Medicine, University of Adelaide, Adelaide, SA 5001, Australia.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Jessup
authors.affiliation: Molecular and Cellular Neuroscience Group, Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Petra
authors.identifier: 0000-0003-4270-2644
authors.initials: P
authors.lastname: Unterweger
authors.affiliation: Molecular and Cellular Neuroscience Group, Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Ravinarayan
authors.initials: R
authors.lastname: Raghupathi
authors.affiliation: Glial Cell Biology and CNS Repair Laboratory, Department of Medical Biochemistry and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Hakan
authors.initials: H
authors.lastname: Muyderman
authors.affiliation: Molecular and Cellular Neuroscience Group, Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Zanin
authors.affiliation: Molecular and Cellular Neuroscience Group, Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Mackenzie
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Pritchard
authors.affiliation: Molecular and Cellular Neuroscience Group, Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA 5042, Australia.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Keating
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins; D005260:Female; D006861:Hydrogen Peroxide / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D009124:Muscle Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide