# Intracellular Electrophysiology: An electrochemical atlas of organelles

> **NIH NIH DP1** · UNIVERSITY OF CHICAGO · 2023 · $1,148,000

## Abstract

PROJECT SUMMARY
 The long-term objective of this proposal is to build an electrochemical atlas of organelles to guide the
rational manipulation of inter-organelle contacts in the context of neurodegenerative diseases. A new mode of
intracellular communication is emerging at the level of organelles, whereby the membranes of two juxtaposed
organelles are physically connected, via protein-protein interactions on their cytoplasmic faces, referred to as
inter-organelle contacts. Ions and small molecules are actively transferred from one organelle to the other across
these contacts, traversing two sealed membranes. Inter-organelle contacts are vital to cell function, tissue
homeostasis and physiology because they regulate processes ranging from lipid metabolism to apoptosis.
However, we still do not know what signals initiate contact formation or what switches on chemical transport
across contacts, nor can we discriminate between functional and dysfunctional contacts. Hence, although we
know of specific mutations in proteins that disrupt contact, leading to diverse neurodegenerative diseases, we
still do not know how to restore these contacts and treat those diseases.
 I posit that the electrochemical states of organelles, alone and in contact, will inform which pathways and
molecules should be targeted to rectify aberrant contacts in disease states. My rationale is that, if we abstract
out the molecular details, inter-organelle contacts resemble neuronal synapses. Even in synapses, ions flow on
cue across two sealed, abutting membranes. Just as ion-transport mechanisms across neuronal membranes
were revealed by Hodgkin and Huxley’s electrochemical model, an analogous model of organelle membranes
will reveal ion flow mechanisms across inter-organelle contacts and which specific flows are impacted in disease.
I propose to build an electrochemical atlas of organelles as a universal reference to study contacts in health and
disease. This atlas will be a compendium of equations comprising electrochemical models of major organelles,
alone and in contact. By enabling us to discriminate normal and aberrant contacts, I envisage the atlas will reveal
common pathways across diseases that can be targeted to restore contacts with impacted ion flows.
 The inability to assay ions or voltage in organelles has prevented the development of electrochemical
models of their membranes. Over the last decade, my lab developed a chemical platform to quantify ions and
voltage in organelles. By integrating electrophysiology to this platform, I propose to now map out the
electrochemical characteristics of organelle membranes in isolation and in contact, and make an electrochemical
atlas of organelles. We will apply the atlas to elucidate how Ca2+ flow across aberrant contacts between the
endoplasmic reticulum and the lysosome can be rectified to restore lysosomal Ca2+ in parkinsonism.
Dysregulated lysosomal Ca2+ is a common factor across many neurodegenerative diseases and the v...

## Key facts

- **NIH application ID:** 10693891
- **Project number:** 5DP1GM149751-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Yamuna Krishnan
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,148,000
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693891

## Citation

> US National Institutes of Health, RePORTER application 10693891, Intracellular Electrophysiology: An electrochemical atlas of organelles (5DP1GM149751-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693891. Licensed CC0.

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