Mitochondrial phosphatidylethanolamine modulates UCP1 to promote brown adipose thermogenesis
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Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist–induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PE-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | eade7864 |
| Tidsskrift | Science Advances |
| Vol/bind | 9 |
| Udgave nummer | 8 |
| Antal sider | 15 |
| ISSN | 2375-2548 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Acknowledgments: W e thank Diana Lim from University of Utah Molecular Medicine for assistance with the figures. Research reported in this publication used the Health Sciences Center Core Facilities at the University of Utah. Funding: This work was supported by NIH grants DK107397, DK127979, GM144613, and AG074535 to K.F .; DK130555 to A.D.P .; DK091317 to M.J.L.; DK103930 to C.J.V .; DK115867 and DK132239 to I.J.L.; GM131854 and CA228346 to J.R.; HL141353 and HL165797 to D.C.; S10 OD016232, S10 OD021505, and U54 DK110858 to University of Utah Metabolomics Core Facility; American Heart Association grant 19PRE34380991 to J.M.J.; Howard Hughes Medical Institute to J.R.; Jane Coffin Childs Memorial Fund to J.T .M.; Nora Eccles Treadwell Foundation to D.C.; and Department of Defense W81XWH-19-1-0213 to K.H.F .-W . Author contributions: J.M.J., A.D.P ., Z.G.-H., and K.F . conceived the project and designed the experiments. J.M.J. and A.D.P . conducted the majority of experiments for this manuscript. E.G.S., V .P ., C.J.V ., and Z.G.-H. assisted with generation of mouse models. J.A.M. and J.E.C. conducted lipidomic mass spectrometry. E.B., M.J.L., A.J.-R., K.H.F .-W ., and D.C. assisted with mitochondrial energetics experiments. J.T .M., J.R., A.S., I.J.L., K.H.F .-W ., and D.C. provided assistance with experimental design. A.D.P . and K.F . wrote the manuscript. This manuscript was reviewed by all authors, revised, and given approval by all authors for publication. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The CLS conditional knockout mice can be provided by the University of Copenhagen pending scientific review and completed material transfer agreement. Requests for the CLS conditional knockout mice should be submitted to Z.G.-H.
Funding Information:
This work was supported by NIH grants DK107397, DK127979, GM144613, and AG074535 to K.F.; DK130555 to A.D.P.; DK091317 to M.J.L.; DK103930 to C.J.V.; DK115867 and DK132239 to I.J.L.; GM131854 and CA228346 to J.R.; HL141353 and HL165797 to D.C.; S10 OD016232, S10 OD021505, and U54 DK110858 to University of Utah Metabolomics Core Facility; American Heart Association grant 19PRE34380991 to J.M.J.; Howard Hughes Medical Institute to J.R.; Jane Coffin Childs Memorial Fund to J.T.M.; Nora Eccles Treadwell Foundation to D.C.; and Department of Defense W81XWH-19-1-0213 to K.H.F.-W.
Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved.
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