PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes

Cell Rep. 2021 Oct 5;37(1):109767. doi: 10.1016/j.celrep.2021.109767.


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: cardiac metabolism switch; cardiomyocyte; carnitine O-palmitoyltransferase 1b; heart failure; hypoxia; long-chain fatty acid; myocardial infarction; prolyl hydroxylase domain protein; voltage-dependent anion channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Fatty Acids
  • Vdac1 protein, mouse
  • PHD3 protein, mouse
  • Procollagen-Proline Dioxygenase
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Voltage-Dependent Anion Channel 1
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase
  • Glucose
  • Carnitine