Language
English
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
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.
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
Published Open-Access
yes
Recommended Citation
Angelini, Aude; Saha, Pradip K; Jain, Antrix; et al., "PHDs/CPT1B/VDAC1 Axis Regulates Long-Chain Fatty Acid Oxidation in Cardiomyocytes" (2021). Faculty and Staff Publications. 1052.
https://digitalcommons.library.tmc.edu/baylor_docs/1052