# The Role of the Mitochondrion in the Metabolic Stress Response to Burn Trauma

> **NIH NIH P20** · ARKANSAS CHILDREN'S HOSPITAL RES INST · 2021 · $292,338

## Abstract

PROJECT SUMMARY
The efficiency of energy transduction in the body has significant implications for body weight regulation and
health. Mitochondrial proton leaks, a process where the proton gradient generated by mitochondria through the
oxidation of substrates and electron transfer is transduced to heat rather than being harnessed to generate
ATP, is a major contributor to metabolic inefficiency in mammals. Thermoregulation is the principal
physiological role ascribed to mitochondria proton leaks, which are responsible for uncoupling around 20-25%
of mitochondrial respiration for ATP production.
There is significant interest in a putative anti-obesity role for mitochondrial proton leaks. This has been driven
by the relatively recent observation that some adult humans possess functional brown adipose tissue (BAT),
and that under certain stress states, subcutaneous white adipose tissue (scWAT) can undergo a browning
response, developing some BAT characteristics. BAT mitochondria are unique in that they express the inner
membrane carrier protein UCP1 (uncoupling protein 1). UCP1-mediated proton leak can almost completely
uncouple BAT mitochondria, where fuel oxidation and respiration can proceed uninhibited and in the absence
of ATP production. In rodent models of prolonged cold stress, UCP1-mediated proton leak in BAT and scWAT
can significantly influence metabolic rate and body mass. However, the role of mitochondrial proton leaks in
metabolic regulation beyond models of chronic cold exposure remains poorly understood.
We propose a series of innovative studies leveraging severe burn injury as a unique clinical model of
hypermetabolism (increased metabolic rate) to probe the role of mitochondrial proton leaks in the regulation of
metabolic rate and body mass. Our overarching hypothesis is that UCP1-mediated proton leak in both BAT
and scWAT contribute to burn-induced hypermetabolism. In specific aim 1, we will further our understanding of
the biochemical basis of hypermetabolism by identifying the tissue specific contributions of mitochondrial
proton leaks to burn-induced hypermetabolism, while also identifying the molecular transducers of these proton
leaks. In addition, stable isotope studies will be used to determine the role of ATP dependent substrate cycling
within scWAT as a novel UCP1-independent mechanism of adipocyte thermogenesis. In specific aim 2, we will
investigate the impact of obesity and diminished capacity of BAT activation and scWAT browning on burn-
induced hypermetabolism. Specifically, we will determine the key changes in the phospholipid and carrier
protein composition of mitochondrial membranes in the liver and skeletal muscle in order to identify key
modulators of mitochondrial proton leak beyond UCP1. This new knowledge may hold clinical value in terms of
identifying targets that may be modulated either to reduce metabolic rate in the context of hypermetabolism, or
to augment mitochondrial inefficiency in the context of nut...

## Key facts

- **NIH application ID:** 10270957
- **Project number:** 2P20GM109096-06
- **Recipient organization:** ARKANSAS CHILDREN'S HOSPITAL RES INST
- **Principal Investigator:** Craig Porter
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $292,338
- **Award type:** 2
- **Project period:** 2016-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10270957

## Citation

> US National Institutes of Health, RePORTER application 10270957, The Role of the Mitochondrion in the Metabolic Stress Response to Burn Trauma (2P20GM109096-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10270957. Licensed CC0.

---

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