# Regulation of mitochondrial calcium uniporter in the heart

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $385,000

## Abstract

PROJECT SUMMARY
Recent discovery of the molecular identity of pore-forming subunit of the mitochondrial Ca2+ uniporter (encoded by
MCU gene) provides new possibilities for applying genetic approaches to study the mitochondrial Ca2+ (mtCa2+)
influx mechanism. T
hough the alteration of
MCU
function and
mtCa2+ overload
are frequently observed in non-
cardiac human diseases,
cardiomyocytes (ACMs)
 and MCU function contribute to the pathology
. Recently, I reported that a post-translational modification (PTM) of MCU (tyrosine
it is still not clear how mtCa2+
in adult
phosphorylation) is one of the critical regulatory mechanisms for upregulating MCU function in ACMs. PTM of MCU
initiates overload, -dependent ROS overproduction and activation of apoptotic signaling under
alpha1-adrenoceptor (alpha1-AR) stimulation, suggesting that PTM of MCU plays an important role in the
development of cardiac dysfunction under Gq-protein-coupled receptor (GqPCR) stimulation, which is one of the
major causes of heart failure (HF) in vivo. In addition to the discovery of the PTM of MCU, I identified a form of
transcriptional/post-transcriptional regulation of MCU, namely the existence of alternative transcript variants (“short-
form” MCU, termed MCU-S) in human and mouse in addition to the original MCU (“long form” MCU, renamed
MCU-L). Importantly, MCU-S is highly expressed in non-excitable cells including adult cardiac fibroblast (ACFs).
Our preliminary data show that introduction of MCU-S enhances the formation of Ca2+-permeable channels at the
plasma membrane (PM). In addition, the PM-localized MCU channel (PM-MCU) formed by MCU-S activates
glycolysis followed by acceleration of ATP production in the cytoplasm, possibly due to the increase in local [Ca2+]c
beneath the PM. These preliminary findings indicate an important role of PM-MCU channels for energy metabolism
especially in non-excitable cells (such as ACFs). We also determined that the manipulation of MCU-S/MCU-L ratio
mtCa2+
mtCa2+
can secondarily modulate the driving force of MCU-channel trafficking to IMM, which eventually
inhibits the mtCa2+
uptake, mtCa2+
 -dependent ROS overproduction and activation of apoptotic signaling under alpha1-AR stimulation.
Therefore, I hypothesize that the MCU gene encodes two isoforms that form both mitochondrial and non-
mitochondrial MCU channels; novel transcript variant MCU-S forms a PM-MCU channels that regulate cell’s
metabolism and inhibits the MCU-channel trafficking to IMM. To test the hypothesis, I will investigate whether MCU-S
forms Ca2+-permeable MCU channels at PM and is involved in the mechanism for the activation of glycolysis to
accelerate ATP production in the cytoplasm in primary ACMs and ACFs (Aim.1). I will next test whether switching
the main variant from MCU-L to MCU-S protects the heart from mtCa2+-overload-mediated apoptotic death, energy
depletion and cardiac dysfunction under GqPCR stimulation in vivo (Aim.2). The outcome of this project is expected
...

## Key facts

- **NIH application ID:** 10145756
- **Project number:** 5R01HL136757-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Jin O-Uchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145756

## Citation

> US National Institutes of Health, RePORTER application 10145756, Regulation of mitochondrial calcium uniporter in the heart (5R01HL136757-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145756. Licensed CC0.

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