# Molecular Mechanism of Mitochondrial Membrane Transport

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $422,530

## Abstract

PROJECT SUMMARY
Mitochondrial calcium (Ca2+) uptake is central to many fundamental physiological processes. It stimulates ATP
production during times of increased metabolic need and provides a Ca2+ sink to modulate Ca2+-mediated
signaling locally within a cell. Mitochondrial Ca2+ concentrations also regulate apoptosis and dysregulation––
specifically, Ca2+ overload––is a hallmark of pathologies ranging from neuronal excitotoxicity to heart failure and
some epilepsies to muscular dystrophies. Yet despite the importance of mitochondrial Ca2+ uptake in normal
physiology and disease, the molecular machinery mediating this process is relatively recently identified and many
fundamental questions remain to be answered.
 The main route of Ca2+ influx to mitochondria is a channel called mitochondrial calcium uniporter, which
includes the ubiquitous pore-forming subunit MCU and, depending on the species, several regulatory subunits
(termed “uniplex” when in complex). This novel channel is highly selective for Ca2+, and its activity is tightly
regulated by cytosolic Ca2+ concentration.
 My group recently determined a high-resolution crystal structure for a fungal MCU that defined a novel
channel architecture and revealed a high-affinity Ca2+-binding site. Moreover, our cryo-EM structure of the human
uniplex holocomplex revealed its architecture and hints at the mechanisms by which it is regulated. With these
structures and the methods we developed, my lab is uniquely poised to embark on the mechanistic
understanding of the mitochondrial calcium uniporter.
 Here, we propose to: 1) elucidate the structural and biophysical basis of ion selectivity, conduction and
inhibition; 2) understand mechanisms of the channel gating and the long-range modulation; and 3) probe the
molecular basis of Ca2+-dependent regulation of the uniplex.
 These results will give us much needed mechanistic insights into the activity and regulation of mitochondrial
calcium uniporter, expanding our understanding of general principles of Ca2+ channels. In addition, they should
provide a strong framework to aid the design of MCU inhibitors, which may represent promising treatments for
diseases and pathologies marked by MCU dysregulation and mitochondrial Ca2+ overload.
!

## Key facts

- **NIH application ID:** 10187602
- **Project number:** 5R01GM138590-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Liang Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $422,530
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187602

## Citation

> US National Institutes of Health, RePORTER application 10187602, Molecular Mechanism of Mitochondrial Membrane Transport (5R01GM138590-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10187602. Licensed CC0.

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