PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes.
Cell Rep
; 37(1): 109767, 2021 10 05.
Article
in En
| MEDLINE
| ID: mdl-34610308
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 ß-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 ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carnitine O-Palmitoyltransferase
/
Procollagen-Proline Dioxygenase
/
Voltage-Dependent Anion Channel 1
/
Fatty Acids
/
Hypoxia-Inducible Factor-Proline Dioxygenases
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cell Rep
Year:
2021
Document type:
Article
Affiliation country: