Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria
Open accessAbstract
Mitochondrial uncoupling protein 1 (UCP1) is responsible for nonshivering thermogenesis in brown adipose tissue (BAT). Upon activation by long-chain fatty acids (LCFAs), UCP1 increases the conductance of the inner mitochondrial membrane (IMM) to make BAT mitochondria generate heat rather than ATP. Despite being a member of the family of mitochondrial anion carriers (SLC25), UCP1 is believed to transport H(+) by an unusual mechanism that has long remained unresolved. Here, we achieved direct patch-clamp measurements of UCP1 currents from the IMM of BAT mitochondria. We show that UCP1 is an LCFA anion/H(+) symporter. However, the LCFA anions cannot dissociate from UCP1 due to hydrophobic interactions established by their hydrophobic tails, and UCP1 effectively operates as an H(+) carrier activated by LCFA. A similar LCFA-dependent mechanism of transmembrane H(+) transport may be employed by other SLC25 members and be responsible for mitochondrial uncoupling and regulation of metabolic efficiency in various tissues.
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Free fatty acids resulting from lipolysis are used both as energy substrates and as activators of UCP1 to uncouple ATP production from mitochondrial respiration into heat.
“Free fatty acids, resulting from lipolysis, are used both as energy substrates and as activators of UCP1 to uncouple ATP production from mitochondrial respiration into heat 73, 85.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [85]
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- Authors
- Fedorenko, A., Lishko, P. V., & Kirichok, Y.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Kirichok, Yuriy
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 151
- Issue
- 2
- Pages
- 400-413
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3782081
- OpenAlex
- W2047306805
- Cited by
- 968
- References
- 47
- Citations by year
- 2026: 47 · 2025: 79 · 2024: 88 · 2023: 89 · 2022: 92 · 2021: 88 · 2020: 101 · 2019: 76 · 2018: 66 · 2017: 67 · 2016: 56 · 2015: 56 · 2014: 41 · 2013: 20
- FWCI
- 25.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Larry L. Hillblom Foundation
- National Institutes of Health (1dp2od004656-01)
- University of California, San Francisco
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- UCP1, brown adipose tissue, long-chain fatty acids, mitochondrial uncoupling, non-shivering thermogenesis, proton transport, hydrophobic interactions, inner mitochondrial membrane
- MeSH terms
- Uncoupling Protein 1, Animals, Binding Sites, Adipose Tissue, Brown, Cytoplasm, Fatty Acids, Ion Channels, Protons, Purines, Patch-Clamp Techniques, Mitochondrial Proteins, Mitochondrial Membranes, Mice
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