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.
Highlights
Neurons depend heavily on mitochondria to buffer cytosolic calcium (Ca2+) concentrations and meet the dynamic metabolic demands imposed by neurotransmission[1,2,3]
We show that conditional mitochondrial calcium uniporter (MCU) deletion in Thy1-expressing neurons renders mice resistant to HI brain injury without producing metabolic compensations observed in global MCU (G-MCU) nulls
Preserved sensorimotor function for TMX/SLICKH/MCUfl/fl/HI mice was accompanied by decreased neuronal damage detected by Fluoro-Jade C (FJ) staining in the CA1 region of the dorsal hippocampus, dorsolateral striatum, and anterior motor cortex compared with controls animals (Fig. 1c–k)
Summary
Neurons depend heavily on mitochondria to buffer cytosolic calcium (Ca2+) concentrations and meet the dynamic metabolic demands imposed by neurotransmission[1,2,3]. Genetic identification of the MCU in 201114,15 has enabled the generation of various genetic mouse lines in which MCU activity is blocked by either global MCU (G-MCU) deletion[13] or cardiac-specific expression of a dominant-negative MCU (DNMCU)[16,17] or inducible cardiac-specific MCU ablation at maturity[18,19]. Experimentation with these genetic lines has shown that conditional, but not constitutive (G-MCU nulls or DN-MCU mice), MCU inhibition protects the heart from ischemic/reperfusion injury[13,16,17,18,19]. The precise nature of the compensations that comprise the resistance of G-MCU nulls to ischemic injury are unclear
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