Tamoxifen-induced knockdown of the mitochondrial calcium uniporter in Thy1-expressing neurons protects mice from hypoxic/ischemic brain injury article

Matthew Nichols, Evgeny Pavlov, George S. Robertson

Research output: Contribution to journalArticle

Abstract

The mitochondrial calcium uniporter (MCU) mediates high-capacity mitochondrial calcium uptake that stimulates energy production. However, excessive MCU activity can cause ischemic heart injury. To examine if the MCU is also involved in hypoxic/ischemic (HI) brain injury, we have generated conditional MCU knockout mice by tamoxifen (TMX) administration to adult MCU-floxed (MCUfl/fl) mice expressing a construct encoding Thy1-cre/ERT2-eYFP. Relative to TMX/Thy1-cre/ERT2-eYFP controls, HI-induced sensorimotor deficits, forebrain neuron loss and mitochondrial damage were decreased for conditional MCU knockout mice. MCU knockdown by siRNA-induced silencing in cortical neuron cultures also reduced cell death and mitochondrial respiratory deficits following oxygen-glucose deprivation. Furthermore, MCU silencing did not produce metabolic abnormalities in cortical neurons observed previously for global MCU nulls that increased reliance on glycolysis for energy production. Based on these findings, we propose that brain-penetrant MCU inhibitors have strong potential to be well-tolerated and highly-efficacious neuroprotectants for the acute management of ischemic stroke.

Original languageEnglish (US)
Article number607
JournalCell Death and Disease
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2018

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Tamoxifen
Brain Injuries
Neurons
Knockout Mice
mitochondrial calcium uniporter
Heart Injuries
Neuroprotective Agents
Glycolysis
Prosencephalon
Small Interfering RNA
Cell Death
Stroke
Oxygen
Calcium
Glucose
Brain

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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Tamoxifen-induced knockdown of the mitochondrial calcium uniporter in Thy1-expressing neurons protects mice from hypoxic/ischemic brain injury article. / Nichols, Matthew; Pavlov, Evgeny; Robertson, George S.

In: Cell Death and Disease, Vol. 9, No. 6, 607, 01.06.2018.

Research output: Contribution to journalArticle

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