Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.

Fatty Acids / metabolism Malonyl Coenzyme A / metabolism Carnitine O-Palmitoyltransferase / genetics Oxidation-Reduction Mitochondria / metabolism
CPT1 fatty acid oxidation fission fusion mitochondrial dynamics

Journal

The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664

Informations de publication

Date de publication:
01 06 2023
Historique:
revised: 17 01 2023
received: 29 06 2022
accepted: 02 02 2023
medline: 2 6 2023
pubmed: 15 3 2023
entrez: 14 3 2023
Statut: ppublish

Résumé

Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.

Identifiants

DOI: 10.15252/embj.2022111901 PMID: 36917141 PMC: PMC10233380
pubmed: 36917141
doi: 10.15252/embj.2022111901
pmc: PMC10233380
doi:

Substances chimiques

Fatty Acids 0
Malonyl Coenzyme A 524-14-1
Carnitine O-Palmitoyltransferase EC 2.3.1.21

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e111901

Subventions

Organisme : NIA NIH HHS
ID : R21 AG063373
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA026914
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099618
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA171400
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM138003
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK078081
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA219850
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063491
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA232056
Pays : United States

Informations de copyright

© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

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Auteurs

Jennifer Ngo (J)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
Department of Molecular and Medical Pharmacology, UCLA, CA, Los Angeles, USA.
Department of Chemistry & Biochemistry, UCLA, CA, Los Angeles, USA.
Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
ORCID: 0000-0002-5829-6866

Dong Wook Choi (DW)

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.
Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, South Korea.

Illana A Stanley (IA)

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.

Linsey Stiles (L)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
Department of Molecular and Medical Pharmacology, UCLA, CA, Los Angeles, USA.

Anthony J A Molina (AJA)

Division of Geriatrics and Gerontology, UCSD School of Medicine, CA, La Jolla, USA.
ORCID: 0000-0002-5786-4622

Pei-Hsuan Chen (PH)

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.

Ana Lako (A)

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.

Isabelle Chiao Han Sung (ICH)

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.
Yale-NUS College, University Town, NUS, Singapore.
ORCID: 0000-0002-1449-4836

Rishov Goswami (R)

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.
ORCID: 0000-0002-3334-8818

Min-Young Kim (MY)

Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, South Korea.

Nathanael Miller (N)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
Obesity Research Center, Molecular Medicine, Boston University School of Medicine, MA, Boston, USA.
ORCID: 0000-0001-9658-9697

Siyouneh Baghdasarian (S)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.

Doyeon Kim-Vasquez (D)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.

Anthony E Jones (AE)

Department of Molecular and Medical Pharmacology, UCLA, CA, Los Angeles, USA.
ORCID: 0000-0003-2058-6021

Brett Roach (B)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.

Vincent Gutierrez (V)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.

Karel Erion (K)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.

Ajit S Divakaruni (AS)

Department of Molecular and Medical Pharmacology, UCLA, CA, Los Angeles, USA.
ORCID: 0000-0002-2528-9651

Marc Liesa (M)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
Department of Molecular and Medical Pharmacology, UCLA, CA, Los Angeles, USA.
Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
Molecular Biology Institute of Barcelona, IBMB-CSIC, Barcelona, Spain.
ORCID: 0000-0002-5909-8570

Nika N Danial (NN)

Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, MA, Boston, USA.
Department of Medicine, Harvard Medical School, MA, Boston, USA.
ORCID: 0000-0003-4842-1827

Orian S Shirihai (OS)

Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, Molecular Biology Institute, UCLA, CA, Los Angeles, USA.
Department of Molecular and Medical Pharmacology, UCLA, CA, Los Angeles, USA.
ORCID: 0000-0001-8466-3431

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Classifications MeSH

Recherchemedicale.com › Lipides › Acides gras › Mitochondrial morphology controls fatty acid...
Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › Coenzyme A › Acyl coenzyme A › Malonyl coenzyme A › Mitochondrial morphology controls fatty acid...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Transferases › Acyltransferases › Carnitine acyltransferases › Carnitine O-palmitoyltransferase › Mitochondrial morphology controls fatty acid...
Recherchemedicale.com › Métabolisme › Métabolisme énergétique › Oxydoréduction › Mitochondrial morphology controls fatty acid...
Recherchemedicale.com › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › Mitochondrial morphology controls fatty acid...