Mitochondrial Ca 2+ uniporter b (MCUb) regulates neuronal Ca 2+ dynamics and resistance to ischemic stroke

Tam Nguyen; Zhihong Lin; Nirav Dhanesha; Rakesh B Patel; Mallorie Lane; Grant C Walters; Leonid P Shutov; Stefan Strack; Anil K Chauhan; Yuriy M Usachev

doi:10.1016/j.ceca.2025.103013

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Mitochondrial Ca 2+ uniporter b (MCUb) regulates neuronal Ca 2+ dynamics and resistance to ischemic stroke

Journal article

Peer reviewed

Mitochondrial Ca 2+ uniporter b (MCUb) regulates neuronal Ca 2+ dynamics and resistance to ischemic stroke

Tam Nguyen, Zhihong Lin, Nirav Dhanesha, Rakesh B Patel, Mallorie Lane, Grant C Walters, Leonid P Shutov, Stefan Strack, Anil K Chauhan and Yuriy M Usachev

Cell calcium (Edinburgh), Vol.128, 103013

02/27/2025

DOI: 10.1016/j.ceca.2025.103013

PMCID: PMC12094165

PMID: 40058292

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Abstract

Mitochondrial Ca2+ transport regulates many neuronal functions including synaptic transmission, ATP production, gene expression and neuronal survival. The mitochondrial Ca2+ uniporter (MCU) is the core molecular component of the mitochondrial Ca2+ uptake complex in the inner mitochondrial membrane. MCUb is a paralog of MCU that negatively regulates mitochondrial Ca2+ uptake in the heart and the cells of the immune system. However, the function of MCUb in the brain is largely unknown. Here, we report that MCUb knockout (KO) led to enhanced mitochondrial Ca2+ uptake in cortical neurons. By simultaneously monitoring changes in cytosolic and mitochondrial Ca2+ concentrations, [Ca2+]cyt and [Ca2+]mt, respectively, we also found that MCUb KO reduced the [Ca2+]cyt threshold required to induce mitochondrial uptake in cortical neurons during electrical stimulation. Exposure of cortical neurons to toxic concentrations of glutamate led to a collapse of mitochondrial membrane potential (ΔΨmt) and [Ca2+]cyt deregulation, and MCUb deletion accelerated the development of both events. Furthermore, using the middle cerebral artery occlusion (MCAO) as a model of transient ischemic stroke in mice, we found that MCUb KO significantly increased MCAO-induced brain damage in male, but not female mice. These results suggest that MCUb regulates neuronal Ca2+ dynamics and excitotoxicity and reveal a sex-dependent role of MCUb in controlling resistance to brain damage following ischemic stroke.

Ischemia

Stroke

MCAO

Mitochondria

calcium

MCUb

excitotoxicity

MCU

Details

Title: Subtitle: Mitochondrial Ca 2+ uniporter b (MCUb) regulates neuronal Ca 2+ dynamics and resistance to ischemic stroke
Creators: Tam Nguyen - University of Iowa, Neuroscience and Pharmacology
Zhihong Lin - University of Iowa
Nirav Dhanesha - University of Iowa
Rakesh B Patel - University of Iowa, Internal Medicine
Mallorie Lane - University of Iowa
Grant C Walters - University of Iowa
Leonid P Shutov - University of Iowa
Stefan Strack - University of Iowa
Anil K Chauhan - University of Iowa
Yuriy M Usachev - University of Iowa
Resource Type: Journal article
Publication Details: Cell calcium (Edinburgh), Vol.128, 103013
DOI: 10.1016/j.ceca.2025.103013
PMID: 40058292
PMCID: PMC12094165
NLM abbreviation: Cell Calcium
ISSN: 0143-4160
eISSN: 1532-1991
Publisher: ELSEVIER SCI LTD; London
Grant note: National Institutes of Health: NS125884, NS127428 NIH: GM067795
This work was supported by National Institutes of Health grants NS125884 and NS127428 to Y.M.U. G.C.W. was supported by a pre-doctoral fellowship through NIH T32 Grant GM067795.
Language: English
Date published: 02/27/2025
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Iowa Neuroscience Institute; Anesthesia; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984800201302771

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