# Investigating the molecular mechanisms of Ca2+ selectivity and Ca2+ potentiation of the mitochondrial calcium uniporter

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $46,752

## Abstract

Project Summary/ Abstract
The mitochondrial calcium uniporter mediates Ca2+ uptake into mitochondria and thereby regulates metabolism,
cell death, and cytoplasmic Ca2+ signaling. How the Uniporter catalyzes ion permeation and achieves ion
selectivity are not well understood. The Uniporter is a supercomplex of protein subunits, containing at least:
MCU, EMRE, MICUs 1-3, MCUR1, and MCUb. The mechanism of Ca2+ selectivity and how the subunits control
gating of the channel have not been fully resolved, in part, because of the difficulties associated with studying
the function of the Uniporter in a purified context. The goal of this proposal is to understand the mechanisms of
Ca2+ selectivity and MCUR1 regulation of the Uniporter. I will take a reductionist approach to investigate these
processes using purified components. Through a blend of structural (cryo-EM) and functional
(electrophysiological) approaches, I will determine critical residues for selectivity of Ca2+ ions in the pore and I
will determine if the pore operates in a multi-ion fashion (Aim 1). Additionally, I will determine interactions of
MCU-EMRE-MCUR1 (MER) holocomplex that are involved in gating (Aim 2). I hypothesize that high Ca2+
selectivity through the pore is mediated by a multi-ion pore mechanism (Aim 1) and that MCUR1 promotes Ca2+
uptake through inhibition of Ca2+ dependent inactivation (Aim 2). The complementary use of single-particle cryo-
EM and planar lipid bilayer electrophysiology will define principles that underline ion selectivity and gating.

## Key facts

- **NIH application ID:** 10535187
- **Project number:** 1F31GM143882-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Bryce Delgado
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-07-26 → 2024-07-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535187

## Citation

> US National Institutes of Health, RePORTER application 10535187, Investigating the molecular mechanisms of Ca2+ selectivity and Ca2+ potentiation of the mitochondrial calcium uniporter (1F31GM143882-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10535187. Licensed CC0.

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