| First Author | Angelini A | Year | 2021 |
| Journal | Cell Rep | Volume | 37 |
| Issue | 1 | Pages | 109767 |
| PubMed ID | 34610308 | Mgi Jnum | J:326966 |
| Mgi Id | MGI:6881813 | Doi | 10.1016/j.celrep.2021.109767 |
| Citation | Angelini A, et al. (2021) PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes. Cell Rep 37(1):109767 |
| abstractText | 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 beta-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 beta-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. |
