# Mitochondrial Calcium Signaling in Cell Intrinsic Immunity

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $560,679

## Abstract

PROJECT SUMMARY
The phagocytes of the immune system require a rapid burst of energy to phagocytose and kill pathogens in a timely
manner. Energy demanding macromolecular complexes such as vacuolar ATPase (V-ATPase) and NADPH
oxidase (NOX) complexes are recruited to the phagosome to acidify, oxidize, kill, and digest the pathogenic cargo.
Reprogramming of the metabolic machinery by gene expression is too slow to meet the sharply increased demand
for energy and metabolites. How do the sentinel phagocytes transmit the recognition of pathogens to switch the
primary gears of cellular metabolism so rapidly? Our preliminary data indicated that the Ca2+-selective,
mitochondrial ion channel, MCU, plays a crucial role in the signaling circuits that rapidly connect the sensory
receptors of pathogens to the metabolic outputs necessary for phagosomal killing. Pursuing these tantalizing leads
has now laid a strong scientific foundation to hypothesize that assembly of phagosome-mitochondria proximity
architecture (PMPA) and mitochondrial Ca2+-signaling fuels cell-intrinsic immunity. In Aim1, we define the
mechanisms underlying mitochondria-phagosome interactions triggered by C. albicans. In Aim 2, we define
mechanisms through which mCa2+-signaling is regulated in activated macrophages. In Aim 3, we define the key
metabolic outputs of mCa2+-signaling that drive microbial killing. This research is conceptually innovative because
it unravels fascinating new connections between pathogen mitochondrial physiology, immunometabolism and
microbial killing. Innovations include tools to monitor mCa2+-elevations in primary macrophages executing
phagocytosis and Electron Tomography based 3D reconstructions of Mitochondria-Phagosome interactions. The
research has the potential to reveal design principles that are of salience to other specialized phagocytic processes
such as clearance of apoptotic cells, toxic debris, and synaptic pruning. From a translational/preclinical perspective,
our findings may reveal novel molecular targets and pathways for new immunomodulatory therapies.

## Key facts

- **NIH application ID:** 10424585
- **Project number:** 5R01AI155808-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** BIMAL N. DESAI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $560,679
- **Award type:** 5
- **Project period:** 2021-06-08 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10424585

## Citation

> US National Institutes of Health, RePORTER application 10424585, Mitochondrial Calcium Signaling in Cell Intrinsic Immunity (5R01AI155808-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10424585. Licensed CC0.

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