# Project 4: Mitochondrial Uniporter Regulation can Limit Ischemic Damage

> **NIH NIH P01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $435,875

## Abstract

SUMMARY
Mitochondrial calcium (mCa2+) overload is a central event in myocardial infarction (MI) and heart failure (HF),
causing metabolic derangement, mitochondrial permeability transition pore (MPTP) activation, genetic
reprograming and loss of cells due to necrosis. The Mitochondrial Calcium Uniporter Channel (mtCU) is the
primary mechanism for mCa2+ uptake, located at the inner mitochondrial membrane (IMM), and physiologically
is required for activation of mitochondrial energetic pathways to support contractility during stress (fight-or-flight
response). The mtCU is a multiprotein high-MW channel, ~400-800 kD in size, containing pore-forming,
scaffold and regulatory components. Given the critical roles in metabolism and cell death it is of great scientific
interest to understand the mechanisms regulating mCa2+ uptake. We recently reported that conditional genetic
ablation of MCU, the pore forming subunit of the mtCU, is cardioprotective in an in vivo model of ischemia-
reperfusion (IR) injury, providing evidence of translational potential. Recently a gene paralog of MCU,
CCDC109b (MCUB), was identified as a component of the uniporter and is theorized to negatively regulate
mCa2+ uptake. However, no genetic or in vivo studies have investigated this gene and it's mechanism of action
remains unknown. Given the therapeutic value of deciphering uniporter channel regulation, this proposal will
examine the molecular function of MCUB, and its contribution to mCa2+ dynamics in cardiac physiology and
disease using in vitro and in vivo genetic gain- and loss-of-function approaches. We hypothesize that MCUB is
a stress-responsive regulator of mitochondrial calcium uptake by modulating the composition (members and
stoichiometry) of the mtCU and that therapeutic manipulation of MCUB will reduce pathogenic mCa2+ uptake, as
occurs in IR injury and heart failure (HF).

## Key facts

- **NIH application ID:** 10145774
- **Project number:** 5P01HL147841-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** John William Elrod
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,875
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145774

## Citation

> US National Institutes of Health, RePORTER application 10145774, Project 4: Mitochondrial Uniporter Regulation can Limit Ischemic Damage (5P01HL147841-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10145774. Licensed CC0.

---

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