Mitochondrial phosphatidylethanolamine modulates UCP1 to promote brown adipose thermogenesis

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Abstract

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.

Abstract

Phosphatidylethanolamine performs a previously unknown role in brown adipose thermogenesis by modulating UCP1 activity.

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Most cited references 70

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Author and article information

Contributors

Jordan M. Johnson:

ORCID: https://orcid.org/0000-0002-2971-2322

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Alek D. Peterlin:

ORCID: https://orcid.org/0000-0002-2837-7446

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Enrique Balderas:

ORCID: https://orcid.org/0000-0001-8780-9272

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing

Elahu G. Sustarsic:

ORCID: https://orcid.org/0000-0002-4792-4740

Role: ConceptualizationRole: MethodologyRole: Resources

J. Alan Maschek:

ORCID: https://orcid.org/0000-0003-3217-2299

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation

Marisa J. Lang: Role: Data curationRole: Investigation

Alejandro Jara-Ramos: Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing - original draft

Vanja Panic: Role: Resources

Jeffrey T. Morgan:

ORCID: https://orcid.org/0000-0002-3017-8665

Role: MethodologyRole: VisualizationRole: Writing - review & editing

Claudio J. Villanueva: Role: ConceptualizationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing - review & editing

Alejandro Sanchez: Role: Methodology

Jared Rutter:

ORCID: https://orcid.org/0000-0002-2710-9765

Role: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing - review & editing

Irfan J. Lodhi:

ORCID: https://orcid.org/0000-0002-6246-9862

Role: Methodology

James E. Cox:

ORCID: https://orcid.org/0000-0002-5977-2350

Role: InvestigationRole: Resources

Kelsey H. Fisher-Wellman:

ORCID: https://orcid.org/0000-0002-0300-829X

Role: InvestigationRole: MethodologyRole: Resources

Dipayan Chaudhuri:

ORCID: https://orcid.org/0000-0003-0605-7334

Role: Formal analysisRole: Funding acquisitionRole: MethodologyRole: VisualizationRole: Writing - review & editing

Zachary Gerhart-Hines:

ORCID: https://orcid.org/0000-0003-2981-4991

Role: MethodologyRole: Resources

Katsuhiko Funai:

ORCID: https://orcid.org/0000-0003-3802-4756

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: February 2023

Publication date (Electronic, pub): 24 February 2023

Volume: 9

Issue: 8

Electronic Location Identifier: eade7864

Affiliations

[ ¹ ]Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT, USA.

[ ² ]Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.

[ ³ ]Utah Center for Clinical and Translational Research, University of Utah, Salt Lake City, UT, USA.

[ ⁴ ]Nora Eccles Harrison Cardiovascular Research and Training Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.

[ ⁵ ]Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

[ ⁶ ]Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT, USA.

[ ⁷ ]Department of Biochemistry, University of Utah, Salt Lake City, UT, USA.

[ ⁸ ]Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT, USA.

[ ⁹ ]Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA.

[ ¹⁰ ]Division of Urology, Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

[ ¹¹ ]Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.

[ ¹² ]East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA.

[ ¹³ ]Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.

Author notes

[†]

These authors contributed equally to this work.

[* ]Corresponding author. Email: kfunai@ 123456utah.edu

Author information

Jordan M. Johnson https://orcid.org/0000-0002-2971-2322

Alek D. Peterlin https://orcid.org/0000-0002-2837-7446

Enrique Balderas https://orcid.org/0000-0001-8780-9272

Elahu G. Sustarsic https://orcid.org/0000-0002-4792-4740

J. Alan Maschek https://orcid.org/0000-0003-3217-2299

Jeffrey T. Morgan https://orcid.org/0000-0002-3017-8665

Jared Rutter https://orcid.org/0000-0002-2710-9765

Irfan J. Lodhi https://orcid.org/0000-0002-6246-9862

James E. Cox https://orcid.org/0000-0002-5977-2350

Kelsey H. Fisher-Wellman https://orcid.org/0000-0002-0300-829X

Dipayan Chaudhuri https://orcid.org/0000-0003-0605-7334

Zachary Gerhart-Hines https://orcid.org/0000-0003-2981-4991

Katsuhiko Funai https://orcid.org/0000-0003-3802-4756

Article

Publisher ID: ade7864

DOI: 10.1126/sciadv.ade7864

PMC ID: 9956115

PubMed ID: 36827367

SO-VID: 5d06acbb-0aa6-4caf-9abf-8c116acb082d

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

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