# Stabilizing mitochondria in sepsis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $479,658

## Abstract

Sepsis is the leading cause of death in US noncoronary intensive care units. Two
pathognomonic features of sepsis are a profound defect in cellular oxygen extraction and
inflammation, both of which may have a mitochondrial basis. Although septic subjects have
mitochondrial defects, the molecular mechanisms underlying their injury that disrupt oxygen
consumption and trigger inflammation remain unclear. The mechanistic platform of this
proposal resides on our discovery of a unique molecular model of mitochondrial injury
whereby a new protein, Fbxo48, potently disrupts mitochondrial function to trigger
inflammation by mediating ubiquitin-driven disposal of a crucial cytoprotective, anti-
inflammatory energy sensor, 5′-AMP-activated protein kinase (AMPK). By targeting the C-
terminal molecular signature present in Fbxo48, we designed, synthesized, and tested a
novel class of small molecule Fbxo48 antagonists which stabilize mitochondrial function and
reduces inflammation in murine and human septic models. Hence, in this application we will
first elucidate how bacterial pathogens deplete AMPK through Fbxo48, thereby accentuating
experimental sepsis (Aim 1). We will specifically elucidate how Fbxo48 targets AMPK for its
degradation using complementary in vitro and in vivo genetic models. Next we will optimize
the pharmacologic design and test a novel small molecule that exhibits distinct, and yet
complementary mitochondrial-protective and anti-inflammatory properties in septic models
(Aim 2). These studies will provide a new pathobiologic model of mitochondrial injury that will
serve as a platform for generating small molecule modulators that optimize cellular
bioenergetics and limit inflammation in subjects with severe critical illness.

## Key facts

- **NIH application ID:** 9726032
- **Project number:** 5R01HL098174-09
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Rama K Mallampalli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $479,658
- **Award type:** 5
- **Project period:** 2018-11-29 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9726032

## Citation

> US National Institutes of Health, RePORTER application 9726032, Stabilizing mitochondria in sepsis (5R01HL098174-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9726032. Licensed CC0.

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