# Mitochondrial metabolism in microbial sepsis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $322,920

## Abstract

Project Summary/Abstract
Sepsis is the most common cause of death in intensive care units and represents a major burden to the US
health care system. Microbial infection and trauma are the most common triggers of acute systemic
inflammatory response that eventually leads to end organ failure and mortality in sepsis. Mitochondria, a
highly metabolically active organelle, have been shown to play an essential role in the innate immune function
and inflammatory response. Robust changes in mitochondrial metabolism (mito-metabolism) occur during
clinical and experimental sepsis. However, the signaling mechanism leading to alterations in mito-metabolism
and its functional consequence on the pathogenesis of sepsis are poorly understood. In this Proposal, we aim
to study the detrimental effects of metabolic abnormalities mediated by mitochondrial calcium signaling on the
innate immune function during microbial sepsis. Our preliminary studies identified the mitochondrial calcium
uniporter (MCU), a key calcium channel for mitochondrial calcium uptake, as an essential regulator of bacterial
killing and septic inflammation. We found that genetic ablation of MCU resulted in improved phagosomal
bacterial killing and less interleukin 1β (IL-1β) secretion due to elevated LC3-associated phagocytosis (LAP).
Mechanistically, MCU inhibits the assembly of LAP complex by promoting mitochondrial metabolite acetyl-
coenzyme A (acetyl-CoA) generation via the pyruvate dehydrogenase (PDH). Therefore, blockade of MCU or
PDH function may represent a promising therapeutic regimen for treating microbial sepsis. The goal of the
proposal is to examine the function and mechanism of mitochondrial calcium signaling-mediated mito-
metabolism on phagosomal bacterial killing and inflammation, both of which are key determinants of host
survival during microbial sepsis. We hypothesize that 1) decreased acetyl-CoA generation in Mcu-deficient
macrophages promotes LAP formation via protein acetylation-dependent mechanism; 2) enhanced LAP
formation promotes phagosome member repair mechanism to limit excessive inflammasome-mediated IL-1β
cleavage; 3) pharmacological inhibition of PDH by CPI-613 is effective in the treatment of microbial sepsis.
Cecal ligation and puncture-induced polymicrobial sepsis model will be employed to examine the role and
functions of MCU-mediated acetyl-CoA metabolism. We will test whether PDH inhibition by CPI-613 plays a
protective effect on sepsis-induced mortality, as well as sepsis-induced immunosuppression. Results of these
studies will provide novel insights into the regulation and function of mito-metabolism, which can potentially
lead to the identification of new therapeutic targets in the treatment of microbial sepsis.

## Key facts

- **NIH application ID:** 10018048
- **Project number:** 5R01GM135234-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Haitao Wen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,920
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018048

## Citation

> US National Institutes of Health, RePORTER application 10018048, Mitochondrial metabolism in microbial sepsis (5R01GM135234-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10018048. Licensed CC0.

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