# ER-mitochondrial communication in calcium signaling, energy metabolism and liver disease

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2022 · $145,860

## Abstract

ABSTRACT
The effects of various hormones on oxidative metabolism and other mitochondrial functions, in the liver and other
tissues, are mediated by cytoplasmic [Ca2+] oscillations propagated to the mitochondria. Ca2+ is released to the
cytoplasm from the endoplasmic reticulum (ER) through the IP3 receptors (IP3Rs), which, based on findings
from us and others, expose mitochondria at ER-mitochondria contact sites (ERMCs) to high [Ca2+] nanodomains
to attain activation of the low-affinity mitochondrial Ca2+ uptake sites. ERMCs were also recognized in other
processes including lipid metabolism, organelle dynamics and autophagy. Our work has revealed the physical
support of ERMCs by tethering proteins. We have created synthetic membrane linkers to measure and perturb
ERMCs and local inter-organelle communication in live cells, and provided clues to local calcium and reactive
oxygen species (ROS) signaling. We have also provided these reagents to several hundred laboratories
worldwide, which together have showed the role of interorganellar contacts in a range of paradigms including
metabolism, vesicle dynamics, neuronal and immune functions and linked structural or functional impairments
of the ER-mitochondrial coupling to an array of disorders across organs including the liver (e.g. fatty liver).
However, fundamental questions remain unanswered. ERMCs are dynamically restructured to meet the
continuously changing demands of the cell, but how ERMCs are formed and dissolved is yet to be
determined. IP3R-mediated fluctuations in [Ca2+] might provide a means to control contact formation, given that
elevations of cytoplasmic [Ca2+] stop mitochondrial movements close to the ER through the Ca2+-sensing Miro
proteins, and both the IP3R and Miro proteins, have been implicated as components of interorganellar
complexes. However, the interaction partners and mechanisms are elusive. We hypothesize that IP3Rs and
Miros mediate ERMC formation in an isoform-specific and Ca2+-dependent manner to regulate
physiological functions of hepatocytes. Aims#1&2 will test this hypothesis using novel genetic and
microscopic imaging toolkits that will enable us to specifically and systematically measure and perturb ERMC
forming elements. The effect of genetic perturbations in the liver will be tested by novel, in vivo imaging
approaches. The interactomes of IP3R and Miro will be evaluated primarily by unbiased proteomics, but Bcl-xL
will also be specifically tested as a tether forming partner for the IP3R. Finally, a major limitation in the field of
inter-organellar communication research is that quantitative evaluation of the geometry of nanometer scale
membrane contacts remains difficult. In Aim#3 we will develop and characterize methods of measuring and
describing organelle interface geometry in 2-and 3D electron microscopy data and uncover the structural
features most relevant to calcium transfer. The proposed work will explore the molecular mechanisms of ERMC
dynamics and t...

## Key facts

- **NIH application ID:** 10631482
- **Project number:** 3R01DK125897-02S1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** GYORGY CSORDAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $145,860
- **Award type:** 3
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10631482

## Citation

> US National Institutes of Health, RePORTER application 10631482, ER-mitochondrial communication in calcium signaling, energy metabolism and liver disease (3R01DK125897-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10631482. Licensed CC0.

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