# Calcium homeostasis and cellular fitness in sepsis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $555,116

## Abstract

ABSTRACT
 Two million Americans are hospitalized for sepsis each year, and 1 in 3 die. Those that survive, however,
are not cured. Neurocognitive disorders occur in up to 50%, and cognitive decline continues for up to 8 years.
Sepsis hospitalizations account for a higher proportion of unplanned readmissions than those for myocardial
infarction, heart failure, and COPD. Five-year mortality for sepsis survivors exceeds that for heart failure and
stroke. The mechanisms underlying this persistent loss of health remain to be defined. We hypothesize that
early during sepsis the mitochondrion is restructured as an adaptive mechanism to protect the cell against any
future environmental stress, such as recurrent sepsis. These structural changes impart lasting alterations to
the mitochondrial calcium (Ca2+) homeostasis and metabolism necessary to support a cellular phenotype,
which for a multicellular organism are poorly tolerated and underlie a persistent loss of health.
Our lab has spent nearly two decades studying sepsis to elucidate the Ca2+-dependent mechanisms that
regulate mitochondrial biology to balance Ca2+ homeostasis and ATP generation and preserve cellular health.
We have shown that early after sepsis, mitochondrial depolarization generates a Ca2+ signal. Members of the
family of Ca2+ /calmodulin-dependent protein kinases (CaMK) transduce these Ca2+ signals and work in
tandem to mediate adaptive changes in mitochondrial fission, mitophagy, and oxidative metabolism to lessen
cellular damage. More recently, we observed that sepsis restructures the mitochondrial calcium uniporter
(MCU) complex, imposing long-lasting changes to mitochondrial and cellular Ca2+ homeostasis and
metabolism that perturb cellular and tissue function across the entire organism. We propose that as a
‘learned’ response to sepsis, the cell restructures the MCU complex to counter the potential for Ca2+
overload with future insult; this imparts long-lasting alterations in Ca2+ homeostasis, oxidative
metabolism, and tissue phenotype. Using models of lower-respiratory tract and intraperitoneal infection and
correlative human samples, we propose the following aims:
Aim 1. To study in mice and humans how a restructured MCU complex alters Ca2+ homeostasis and
oxidative metabolism and thereby, the phenotype of each tissue comprising the organism.
Aim 2. To define the mechanisms of mitophagy and protein degradation through the lysosome and
proteasome as underlying causes of the persistent loss of MICU1 expression in murine models of
sepsis and in human sepsis survivors.
This new experimental work will provide foundational knowledge as to how the mechanisms governing
mitochondrial Ca2+ and metabolism are restructured during sepsis to underlie a persistent loss of cellular
phenotype that leads to a progressive loss of health and shortened survival.

## Key facts

- **NIH application ID:** 10500608
- **Project number:** 1R01GM147121-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** MATTHEW Randall ROSENGART
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $555,116
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500608

## Citation

> US National Institutes of Health, RePORTER application 10500608, Calcium homeostasis and cellular fitness in sepsis (1R01GM147121-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10500608. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*