PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes
Aude Angelini,
Pradip K. Saha,
Antrix Jain,
Sung Yun Jung,
Randall L. Mynatt,
Xinchun Pi,
Liang Xie
Affiliations
Aude Angelini
Department of Medicine, Section of Athero & Lipo, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
Pradip K. Saha
Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Diabetes Research Center, Baylor College of Medicine, Houston, TX 77030, USA
Antrix Jain
Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA
Sung Yun Jung
Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, TX 77030, USA
Randall L. Mynatt
Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
Xinchun Pi
Department of Medicine, Section of Athero & Lipo, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
Liang Xie
Department of Medicine, Section of Athero & Lipo, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
Summary: 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.
