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

• Main Authors: Aude Angelini, Pradip K. Saha, Antrix Jain, Sung Yun Jung, Randall L. Mynatt, Xinchun Pi, Liang Xie
• Format: Article
• Language: English
• Published: Elsevier 2021-10-01
• Series: Cell Reports
• Subjects: cardiac metabolism switch; carnitine O-palmitoyltransferase 1b; myocardial infarction; heart failure; hypoxia; long-chain fatty acid
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124721012213

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.