# Redox control over metabolism and mitochondrial bioenergetics directs the  course of acute inflammation and sepsis.

> **NIH NIH R35** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $387,522

## Abstract

SUMMARY
The principal goal of this MIRA proposal from a distinguished PI with many years of uninterrupted NIH R01
funding and productive research in acute inflammation is to address the major gap and unmet need of
understanding how humans survive sepsis, the highly lethal acute systemic inflammatory response driven by
infection. Most sepsis deaths occur during organ and immune failure from dysregulated inflammation. No
molecular-based specific therapies are available for this health dilemma. This proposal will develop a new
and unifying theory of sepsis, according to which a persistent low-energy catabolic state, systemic
inflammation inertia (SII), impedes oxidative metabolism and prevents failing immunity and organs
from regaining the anabolic energy state needed to restore homeostasis. Mechanistically, this proposal's
working model posits that a switch from a pro-oxidant anabolic state to a persistent antioxidant catabolic state
underlies SII. It further theorizes that a functional cysteine thiol-based redox “switchboard” located on key
protein homeostats controls the equilibrium between anabolism and during sepsis, and that its rewiring causes
bioenergetics failure and promotes high mortality sepsis. However, the theory predicts that SII is reversible and
therapeutically targeting key homeostats can restore metabolic balance and enable immune system and organ
recovery and improve sepsis survival. Consistent with the reversibility concept, independently targeted nuclear
NAD+ dependent SIRT1 and mitochondrial PDK1 promote redox and bioenergy equilibrium and increase
survival in a mouse model of sepsis-dependent SII, and proof of principle occurs in human sepsis blood
monocytes. The PI's funded NIGMS and NIAID R01 grants consolidated in this MIRA provided early support
for the energy “supply-and-demand discrepancy” theory of how sepsis so often kills. Consolidating the PI's
research program will maximize understanding and targeted treatment of a major public health dilemma, about
which we are still insufficiently informed and which continues to be a major killer.

## Key facts

- **NIH application ID:** 10149341
- **Project number:** 5R35GM126922-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Charles Emory McCall
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,522
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149341

## Citation

> US National Institutes of Health, RePORTER application 10149341, Redox control over metabolism and mitochondrial bioenergetics directs the  course of acute inflammation and sepsis. (5R35GM126922-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10149341. Licensed CC0.

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