Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 37, Issue 8, Pages 3027-3041Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X16682250
Keywords
Glycolysis; hypoxic preconditioning; mitochondrial calcium uniporter; neuronal bioenergetics; stroke
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Funding
- Heart and Stroke Foundation of Canada
- American Heart Association
- Heart and Stroke Foundation of Canada and Brain Canada
- MS Society of Canada
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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 toWT, cortical neurons. HI reduced forebrain NADH levels more in global MCU nulls thanWT 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.
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