# UCP1 and the regulation of mitochondrial respiration in brown adipose tissue by oxaloacetate

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $315,000

## Abstract

PROJECT SUMMARY
 Control of metabolic flux through the TCA cycle has been investigated dating back many
decades. However, there are issues that still require clarification. One important, but largely
neglected, issue regards the role of oxaloacetate (OAA) inhibition of succinate dehydrogenase
(SDH) in regulating mitochondrial function. Recent findings in my laboratory focused on skeletal
muscle mitochondria show that while low membrane potential (ΔΨ) drives respiration, low ΔΨ
also initiates a sequence of events leading to mitochondrial OAA accumulation, inhibition of
SDH, and consequent inhibition or metabolic “braking” of respiration. Given that low ΔΨ
appears to be the initiating factor, the current proposal is focused on the role of OAA in
regulating respiration in brown adipose tissue (BAT) wherein ΔΨ is intrinsically low due to the
action of uncoupling protein 1 (UCP1).
 Our overall hypothesis is that mitochondrial OAA metabolism and inhibition of SDH is
regulated by definable interactions between UCP1 controlled ΔΨ and downstream events and
that there are physiological consequences. Our aims address three issues. Aim 1 will delineate
molecular events initiated by UCP1-regulated ΔΨ and culminating in OAA inhibition of O2 flux.
Aim 2 examines UCP1 perturbations in live mice to determine if this translates to OAA effects
on mitochondrial and cellular function. Aim 3 attempts to modulate OAA inhibition of SDH in a
way that may prove beneficial towards mitochondrial, cellular, and whole-body metabolism.
 To accomplish our objectives, we will use a novel NMR assay to assess mitochondrial
OAA content as well as other metabolites. A major reason why our knowledge of OAA effects
on respiration is lacking is that OAA is difficult to assay since the metabolite is not stable. In fact,
metabolomics services, whether commercial or in university cores, do not offer quantification of
OAA. Our research will also use a novel adaptation of existing technology that we developed to
assess mitochondrial respiration at clamped concentrations of ADP. In this way, we can assess
mitochodnrial respiration beyond the often-determined state 3 and state 4, which are not
physiological states. Finally, we will use up-to-date mass spectroscopy methods for targeted
metabolite expression and for [13C]isotopomer tracer studies directed at metabolic flux.
 Our project is applicable to the clinical issue of obesity and its complications since
understanding BAT physiology and how it is regulated will add to our overall knowledge of
whole-body energetics.

## Key facts

- **NIH application ID:** 10263284
- **Project number:** 5R01DK123043-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** William Irving Sivitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $315,000
- **Award type:** 5
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263284

## Citation

> US National Institutes of Health, RePORTER application 10263284, UCP1 and the regulation of mitochondrial respiration in brown adipose tissue by oxaloacetate (5R01DK123043-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10263284. Licensed CC0.

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