Fatty Acid Flippase Activity of UCP2 Is Essential for Its Proton Transport in Mitochondria
Open accessAbstract
Modulation of cellular energy expenditure is fundamental to normal and pathological cell growth and differentiation. Mitochondria stores energy as a proton gradient across their inner membrane. Uncoupling proteins (UCPs) can dissipate the gradient to produce heat or regulate metabolite fluxes. UCP-mediated proton currents require fatty acids (FAs) and are blocked by nucleotides, but the molecular basis of these processes is unknown. We find, by nuclear magnetic resonance and functional mutagenesis, that UCP2 can bind FAs laterally through its peripheral site, and this intramembrane molecular recognition is essential for UCP2-catalyzed FA flipping across the membrane, which in turn is essential for proton translocation. The antagonist GDP binds inside the UCP2 cavity and perturbs its conformation, which can displace FA from the peripheral site as a mean of inhibiting proton currents. Our data provide a biophysical perspective of the intricate interplay of UCPs, FA, and nucleotides in determining proton fluxes in mitochondria.
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UCP-2 can only be activated under circumstances such as massive entry of FFAs into mitochondria.
“UCP-2 could then only be activated under some circumstances, such as a massive entry of FFAs into mitochondria [18].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [18]
UCP-2 can induce mitochondrial uncoupling by acting as a fatty acid flippase transporter.
“However, others found that UCP-2 could indeed induce mitochondrial uncoupling by essentially acting as a fatty acid flippase transporter [18].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [18]
UCP-2 activity can be completely blocked by GDP at basal state (100 μM).
“The same authors suggested that UCP-2 activity could be completely blocked by GDP at the basal state (100 µM, which corresponds to the basal intracellular GDP/GTP concentration) [18].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [18]
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- Authors
- Berardi, M. J., & Chou, J. J.
- Affiliations
- Harvard University (US)
- Corresponding author
- Chou, James J.
- ORCID
- Chou, James J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 20
- Issue
- 3
- Pages
- 541-552
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4156518
- OpenAlex
- W1968217511
- Cited by
- 76
- References
- 38
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 11 · 2021: 7 · 2020: 8 · 2019: 11 · 2018: 9 · 2017: 7 · 2016: 5 · 2015: 5 · 2014: 1
- FWCI
- 2.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM094608, U54GM094608)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- UCP2, uncoupling proteins, fatty acid uptake, proton transport, mitochondrial proton gradient, GDP binding, nucleotide inhibition, energy dissipation
- MeSH terms
- Uncoupling Protein 2, Alkanesulfonates, Animals, Fatty Acids, Guanosine Diphosphate, Ion Channels, Mitochondria, Models, Molecular, Protons, Mitochondrial Proteins, Mice
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