Publication Date

10-5-2021

Journal

Cell Reports

DOI

10.1016/j.celrep.2021.109767

PMID

34610308

PMCID

PMC8658754

PubMedCentral® Posted Date

12-9-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Carnitine, Carnitine O-Palmitoyltransferase, Diet, High-Fat, Fatty Acids, Glucose, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Lipid Peroxidation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mutagenesis, Site-Directed, Myocytes, Cardiac, Procollagen-Proline Dioxygenase, Protein Binding, Voltage-Dependent Anion Channel 1

Abstract

Cardiac metabolism is a high-oxygen-consuming process, showing a preference for long-chain fatty acid (LCFA) as the fuel source under physiological conditions. However, a metabolic switch (favoring glucose instead of LCFA) is commonly reported in ischemic or late-stage failing hearts. The mechanism regulating this metabolic switch remains poorly understood. Here, we report that loss of PHD2/3, the cellular oxygen sensors, blocks LCFA mitochondria uptake and β-oxidation in cardiomyocytes. In high-fat-fed mice, PHD2/3 deficiency improves glucose metabolism but exacerbates the cardiac defects. Mechanistically, we find that PHD2/3 bind to CPT1B, a key enzyme of mitochondrial LCFA uptake, promoting CPT1B-P295 hydroxylation. Further, we show that CPT1B-P295 hydroxylation is indispensable for its interaction with VDAC1 and LCFA β-oxidation. Finally, we demonstrate that a CPT1B-P295A mutant constitutively binds to VDAC1 and rescues LCFA metabolism in PHD2/3-deficient cardiomyocytes. Together, our data identify an oxygen-sensitive regulatory axis involved in cardiac metabolism.

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