title: Global ablation of the mitochondrial calcium uniporter increases glycolysis in cortical neurons subjected to energetic stressors.
abstract: The effects of global mitochondrial calcium (Ca2+) uniporter (MCU) deficiency on hypoxic-ischemic (HI) brain injury, neuronal Ca2+handling, bioenergetics and hypoxic preconditioning (HPC) were examined. Forebrain mitochondria isolated from global MCU nulls displayed markedly reduced Ca2+uptake and Ca2+-induced opening of the membrane permeability transition pore. Despite evidence that these effects should be neuroprotective, global MCU nulls and wild-type (WT) mice suffered comparable HI brain damage. Energetic stress enhanced glycolysis and depressed Complex I activity in global MCU null, relative to WT, cortical neurons. HI reduced forebrain NADH levels more in global MCU nulls than WT mice suggesting that increased glycolytic consumption of NADH suppressed Complex I activity. Compared to WT neurons, pyruvate dehydrogenase (PDH) was hyper-phosphorylated in MCU nulls at several sites that lower the supply of substrates for the tricarboxylic acid cycle. Elevation of cytosolic Ca2+with glutamate or ionomycin decreased PDH phosphorylation in MCU null neurons suggesting the use of alternative mitochondrial Ca2+transport. Under basal conditions, global MCU nulls showed similar increases of Ca2+handling genes in the hippocampus as WT mice subjected to HPC. We propose that long-term adaptations, common to HPC, in global MCU nulls compromise resistance to HI brain injury and disrupt HPC.
authors.affiliation: 1 Faculty of Medicine, Department of Pharmacology, Brain Repair Centre, Life Sciences Research Institute, Dalhousie University, Halifax, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Nichols
authors.affiliation: 2 Faculty of Medicine, Department of Physiology and Biophysics, Dalhousie University, Halifax, Canada.
authors.forename: Pia A
authors.initials: PA
authors.lastname: Elustondo
authors.affiliation: 3 Faculty of Medicine, Department of Pathology, Dalhousie University, Halifax, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Warford
authors.affiliation: 1 Faculty of Medicine, Department of Pharmacology, Brain Repair Centre, Life Sciences Research Institute, Dalhousie University, Halifax, Canada.
authors.forename: Aruloli
authors.initials: A
authors.lastname: Thirumaran
authors.affiliation: 4 Department of Basic Sciences, College of Dentistry, New York University, New York, NY, USA.
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Pavlov
authors.affiliation: 1 Faculty of Medicine, Department of Pharmacology, Brain Repair Centre, Life Sciences Research Institute, Dalhousie University, Halifax, Canada.|5 Department of Psychiatry, QEII Health Sciences Centre, Halifax, Canada.
authors.forename: George S
authors.initials: GS
authors.lastname: Robertson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D004734:Energy Metabolism; D005260:Female; D006019:Glycolysis; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D019194:Ischemic Preconditioning; D008297:Male; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture
chemical_list: D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C034703:mitochondrial calcium uniporter; D002118:Calcium
keywords: Glycolysis; hypoxic preconditioning; mitochondrial calcium uniporter; neuronal bioenergetics; stroke