# Structural and Functional Studies of Organellar Ion Channels

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $327,583

## Abstract

ABSTRACT
 Ion transfer across biological membranes is central to nerve excitation, muscle cell contraction, signal
transduction, and hormone secretion. Ion channels play a vital role by providing a passageway within
membranes to allow specific ions to traverse down their electrochemical gradient. The immense physiological
importance of ion channels is reflected in the fact that their dysfunction underlies a variety of disabling human
diseases including seizures, deafness, ataxia, long QT syndrome, and cardiac arrhythmias. There is a long
history of physiological work and a large body of functional and structural data on tetrameric cation channels
that are localized to the plasma membrane, including the K+, Ca2+, Na+, TRP and cyclic nucleotide-gated
channels; however, relatively little is known about organellar cation channels, partly because of the difficulty in
directly measuring their activities in organellar membranes. Currently, there is an emerging research interest in
the recently identified organellar cation channels due to their importance in organelle physiology and cell
signaling. This Maximizing Investigators' Research Award proposal will be focused on our ongoing efforts to
dissect the structural and functional properties of two specific groups of organellar cation channels: the
endolysosomal cation channels and the mitochondrial calcium uniporters. The insights gained from the
proposed studies will facilitate our understanding of how these organellar channels regulate some basic
biological functions of lysosome and mitochondria.
 Endosomes and lysosomes play crucial roles in many biological processes such as protein and lipid
degradation, catabolite export, membrane trafficking, and metabolism-sensing, and defects to these processes
can result in lysosomal storage diseases. These acidic organelles contain various ion channels that control
endolysosomal pH and ionic homeostasis. One major research direction in my lab is designed to reveal the
structural basis of gating and selectivity in endolysosomal cation channels, including two-pore channels
(TPCs), transient receptor potential mucolipin channels (TRPMLs), and the non-canonical TMEM175 K+
channels. Mitochondria can take up large amounts of Ca2+ from cytosol, a process that can modulate ATP
production, alter cytoplasmic Ca2+ dynamics, and trigger cell death. Mitochondrial calcium uptake is mediated
by the mitochondria calcium uniporter (MCU), a highly selective Ca2+ channel that is localized to the inner
mitochondrial membrane. In humans, the uniporter functions as a protein complex consisting of at least four
components: the pore-forming MCU, the essential membrane-spanning subunit EMRE, and the Ca2+-sensing
gate-keeping proteins MICU1 and MICU2. Another major project in the lab aims to reveal the structural basis of
the human MCU complex assembly and the channel regulation. Our experimental approach utilizes single
particle cryo-electron microscopy (cryo-EM) and protein crystallo...

## Key facts

- **NIH application ID:** 10167530
- **Project number:** 1R35GM140892-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** YOUXING JIANG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $327,583
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167530

## Citation

> US National Institutes of Health, RePORTER application 10167530, Structural and Functional Studies of Organellar Ion Channels (1R35GM140892-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10167530. Licensed CC0.

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