Mitochondrial Calcium Uniporter (MCU) is Involved in an Ischemic Postconditioning Effect Against Ischemic Reperfusion Brain Injury in Mice

Overview

Journal Cell Mol Neurobiol

Publisher Springer

Specialties Cell Biology
Molecular Biology
Neurology

Date 2024 Apr 3

PMID 38568450

Authors

Hiromitsu Sasaki

Ichiro Nakagawa

Takanori Furuta

Shohei Yokoyama

Yudai Morisaki

Yasuhiko Saito

Hiroyuki Nakase

Affiliations

Soon will be listed here.

Abstract

The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-K) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs (p = 0.014), NMDAR currents (p < 0.001), intracellular Ca concentration (p < 0.001), and dead cells (p < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC (p = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca concentrations against I/R injury.

Citing Articles

Effects of a mitochondrial calcium uniporter and P-selectin inhibitors on neural injury induced by global cerebral ischemia-reperfusion in male rats.

Javanmardi S, Moradpour F, Veisi M, Omidian N, Kavyannejad R Metab Brain Dis. 2025; 40(3):150.

PMID: 40085331 DOI: 10.1007/s11011-025-01570-5.

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