Global ablation of the mitochondrial calcium uniporter increases glycolysis in cortical neurons subjected to energetic stressors

Matthew Nichols, Pia A. Elustondo, Jordan Warford, Aruloli Thirumaran, Evgeny V. Pavlov, George S. Robertson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3027-3041
Number of pages15
JournalJournal of Cerebral Blood Flow and Metabolism
Volume37
Issue number8
DOIs
StatePublished - Aug 1 2017

Keywords

  • Glycolysis
  • hypoxic preconditioning
  • mitochondrial calcium uniporter
  • neuronal bioenergetics
  • stroke

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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