# Molecular Physiology of Mitochondrial Calcium Uniporter

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $339,900

## Abstract

Project Summary
The mitochondrial calcium uniporter complex (MCUcx) is a highly-selective, tetrameric Ca2+ channel that plays
a primary role in transporting Ca2+ from the cytoplasm into the mitochondrial matrix. Although Ca2+ uptake by
mitochondria plays a crucial role in stimulating ATP production, matrix Ca2+ overload can trigger opening of the
mitochondrial permeability transition pore, leading to cell death. MCU dysfunction has been implicated in
several pathological conditions such as heart failure, ischemia–reperfusion injury, neurodegeneration, cancer
and skeletal muscle dystrophies. Recent biochemical and structural studies have shown that the MCUcx is a
macromolecular complex composed of a pore-forming MCU subunit, an essential subunit EMRE, and EF-hand
domain-containing MICU1–3 subunits. How each subunit of the MCU complex comes together and regulates
mitochondrial Ca2+ entry has been the focus of many recent studies. Using direct mitochondrial patch-clamp
methodology and an innovative heterologous expression system, we recently performed a comprehensive
structure–function analysis of the MCUcx in the inner mitochondrial membrane. This expression system
consists of gene knockout of each individual subunit of the MCUcx (more than 6 different knockout lines were
generated by CRISPR/cas9) and is readily amenable to different patch-clamp configurations with a high
success rate. Using this system and the patch-clamp technique, we propose to answer central questions in the
field: 1) Where is the MCU gate, and how is this gate regulated by Ca2+ and MCU accessory subunits? and 2)
How do the unique features in the MCU macromolecular structures (as revealed by recent structural studies)
relate to MCU gating and function? Accomplishment of the aims of this proposal will provide better
understanding of the mechanisms that regulate Ca2+ entry via the MCU and create an essential framework for
the development of pharmacological interventions that target MCU gating for therapeutic purposes.

## Key facts

- **NIH application ID:** 10863964
- **Project number:** 5R01GM145806-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Vivek Garg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,900
- **Award type:** 5
- **Project period:** 2023-06-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863964

## Citation

> US National Institutes of Health, RePORTER application 10863964, Molecular Physiology of Mitochondrial Calcium Uniporter (5R01GM145806-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863964. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*