# Molecular Mechanisms of Mitochondrial Uncoupling and Thermogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $443,800

## Abstract

Project Summary
Through substrate oxidation, mitochondria generate a high potential across the inner mitochondrial membrane
(IMM). The energy of this potential is usually converted into ATP by the mitochondrial ATP synthase, but a
fraction is dissipated as heat due to the presence of a H+ leak across the IMM. This mitochondrial H+ leak is
mediated by specialized proteins of the IMM, such as uncoupling protein 1 (UCP1), and it has important
physiological functions. It controls the metabolic efficiency of the body, helps to support the core body
temperature, and reduces mitochondrial production of reactive oxygen species to protect against oxidative
damage. The mitochondrial H+ leak is considered to be important in protective mechanisms against obesity,
diabetes, and age-related degenerative disorders as well as against pathological conditions involving
mitochondrial oxidative stress such as ischemia-reperfusion. Despite its physiological and pathophysiological
significance, the mitochondrial H+ leak remains poorly understood, primarily due to the lack of direct methods
to study it. We recently developed a method that removes this technical barrier and for the first time allows
direct patch-clamp recording of H+ leak currents from the whole IMM. This method helped us resolve long-
standing questions about the mechanism of the UCP1-dependent thermogenic H+ leak across the IMM of
brown fat. In this application, we propose to use the patch-clamp technique to further characterize the
mitochondrial H+ leak in several tissues that play important roles in thermogenesis and energy metabolism.
The specific aims of this proposal are to: 1) identify the protein(s) responsible for the mitochondrial H+ leak in
non-adipose tissues; 2) characterize the mechanism of the fatty acid-activated mitochondrial H+ leak via the
adenine nucleotide translocator (ANT); 3) characterize the mechanism of the mitochondrial H+ leak induced by
protonophores DNP and FCCP. Accomplishment of these specific aims will help us elucidate the principal
mechanism that regulates metabolic efficiency and thermogenesis, and such knowledge will aid the
development of therapeutic interventions to control obesity, diabetes, and age-related degenerative disorders.

## Key facts

- **NIH application ID:** 9838759
- **Project number:** 5R01GM118939-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Yuriy Kirichok
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,800
- **Award type:** 5
- **Project period:** 2017-03-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838759

## Citation

> US National Institutes of Health, RePORTER application 9838759, Molecular Mechanisms of Mitochondrial Uncoupling and Thermogenesis (5R01GM118939-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838759. Licensed CC0.

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