Angelini 2021 Cell Rep
| Angelini A, Saha PK, Jain A, Jung SY, Mynatt RL, Pi X, Xie L (2021) PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes. Cell Rep 37:109767. |
Angelini Aude, Saha Pradip K, Jain Antrix, Jung Sung Yun, Mynatt Randall L, Pi Xinchun, Xie Liang (2021) Cell Rep
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 Ξ²-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 Ξ²-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. β’ 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 β’ Bioblast editor: Plangger M
Labels: MiParea: Respiration
Pathology: Cardiovascular
Stress:Ischemia-reperfusion
2021-10
