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

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.

• Authors: Matthew Nichols, Evgeny V Pavlov, George S Robertson
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 6 Pg. 606 (05 22 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29789575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels
• Pyruvate Dehydrogenase Complex
• Thy-1 Antigens
• mitochondrial calcium uniporter
• Tamoxifen
• Glucose
• Oxygen

Topics

• Animals
• Calcium Channels (deficiency, metabolism)
• Cell Respiration (drug effects)
• Cell Survival (drug effects)
• Gene Knockdown Techniques
• Glucose (deficiency)
• Glycolysis (drug effects)
• Hypoxia-Ischemia, Brain (metabolism, physiopathology, prevention & control)
• Mice, Inbred C57BL
• Mitochondria (drug effects, metabolism, ultrastructure)
• Motor Activity (drug effects)
• Neurons (drug effects, metabolism, pathology)
• Oxygen
• Phosphorylation (drug effects)
• Pyruvate Dehydrogenase Complex (metabolism)
• Tamoxifen (pharmacology)
• Thy-1 Antigens (metabolism)