# Regulation and function of mitochondrial calcium uniporter in the heart

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2022 · $735,641

## Abstract

Summary
Heart failure is the leading cause of death and a huge burden on health care in the United States. Recently,
impaired energy metabolism has emerged as a key contributor to the failure of the heart’s pumping function, and
new breakthroughs in metabolic research and mitochondrial biology have been reported. One of the key
mechanisms for regulating mitochondrial function in the beating heart is calcium uptake through mitochondrial
calcium uniporter (MCU). Surprisingly, MCU knockout mice exhibited normal phenotype, heart performance and
mitochondrial function, indicating that MCU is dispensable in the normal heart. Pathological significance of MCU
or mitochondrial calcium in the hypertrophic and failing heart is also elusive and highly debated. Finally, how
MCU gene expression is regulated in the heart remains unexplored. These gaps in knowledge diminished the
initial excitement ignited by the discovery of the molecular identity of MCU. Our promising preliminary results
show that MCU expression is high in perinatal heart and in the chronically stressed adult heart via transcriptional
regulation by calcium-calmodulin dependent protein kinase II δB (CaMKIIδB). Loss-of-function and gain-of-
function approaches reveal that MCU plays a compensatory role in heart hypertrophy and dysfunction through
modulating cytosolic calcium and cell death pathways. Unexpectedly, knockout MCU during the perinatal stage
worsened pressure overload-induced heart dysfunction in adult mice. Based on these results, we hypothesize
that MCU expression is strategically enhanced in the perinatal heart and in the stressed adult heart to ameliorate
pathological heart remodeling. We will test this hypothesis in three Specific Aims. We will determine the
molecular mechanisms by which CaMKIIδB regulates MCU gene expression. We will answer why cardiac
hypertrophy and dysfunction are alleviated by MCU upregulation but aggravated by MCU inhibition. Furthermore,
we will investigate the regulation of MCU in perinatal heart and how MCU limits pressure overload-induced
dysfunction in the adult heart. Results of this study will depict a full mechanism by which MCU gene expression
is fine tuned in the heart. This study also aims to uncover novel roles of MCU in perinatal heart and in the
hypertrophic adult heart that counteract cardiac remodeling induced by multiple stresses.

## Key facts

- **NIH application ID:** 10705327
- **Project number:** 1R56HL153124-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Wang Wang
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $735,641
- **Award type:** 1
- **Project period:** 2022-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705327

## Citation

> US National Institutes of Health, RePORTER application 10705327, Regulation and function of mitochondrial calcium uniporter in the heart (1R56HL153124-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10705327. Licensed CC0.

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