# Targeting ER-mitochondrial calcium signaling to promote healthier aging

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2024 · $324,925

## Abstract

Project Summary/Abstract
Fundamental gaps remain in our understanding of the cell biological mechanisms that drive mitochondrial decline
and associated age-related diseases. Organelles like the mitochondria and endoplasmic reticulum (ER) are
physically and functionally linked, in part via sites of membrane contact. These lines of communication between
mitochondria and other organelles represent an understudied avenue by which to therapeutically target
mitochondrial function. Our long-term goal is to understand the physiological roles of inter-organelle
communication during aging and age-related disease. In pursuit of that goal, our objective in this application is
to determine how the ER regulates mitochondrial health during aging through its role as a platform for calcium
signaling. We have exploited the simple anatomy of C. elegans and experimental advantages in genetics and
microscopy to lay a foundation in this model for the study of ER-mitochondrial interactions. Similar to mammals,
the worm ER calcium efflux channel, inositol triphosphate receptor (InsP3R), exerts potent control over
mitochondrial bioenergetics, and we have extended the roles of InsP3R to regulation of mitochondrial gene
expression and dynamics in the worm as well. Furthermore, the InsP3R regulates lifespan in C. elegans through
mechanisms that depend upon mitochondrial function. Here we will test the hypothesis that ER remodeling in
aging animals acts to trigger mitochondrial dysfunction and organismal decline by promoting aberrant subcellular
calcium signaling and dynamics. To test this hypothesis, we will first determine whether the InsP3R is a cell
autonomous regulator of mitochondrial function and lifespan. Secondly, we will identify the molecular
mechanisms linking InsP3R activity to the diverse changes observed in mitochondrial behavior. Finally, we will
determine how organellar remodeling of the calcium flux machineries initiates age-onset mitochondrial
dysfunction. By revealing the mechanisms by which ER signaling governs mitochondrial health at the organismal
level, these results will open new therapeutic avenues in treating mitochondrial pathologies.

## Key facts

- **NIH application ID:** 10827987
- **Project number:** 5R01AG073354-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Kristopher Burkewitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $324,925
- **Award type:** 5
- **Project period:** 2022-06-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827987

## Citation

> US National Institutes of Health, RePORTER application 10827987, Targeting ER-mitochondrial calcium signaling to promote healthier aging (5R01AG073354-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10827987. Licensed CC0.

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