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

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 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.

SUBMITTER: Angelini A

PROVIDER: S-EPMC8658754 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare, autosomal recessive genetic disorders that impair conversion of long-chain fatty acids into energy. Here we describe the impact of LC-FAOD in terms of effects on work and school, absenteeism and presenteeism at work, importance of symptoms, physical activity, participation in social activities, and quality of life (QoL). A convenience sample of adults (≥18 years) and caregivers of patients with LC-FAOD was invited to take the online survey (Confirmit). To be included, patients must have been receiving medical care from a healthcare provider for their LC-FAOD, and caregivers must not have been compensated for their care. Degree of physical activity, represented by metabolic equivalents (METs), was calculated using the NHANES Physical Activity Questionnaire. Absenteeism and presenteeism at work were calculated using the WHO Health Productivity Questionnaire. QoL was assessed using the 12-Item Short Form of the Medical Outcomes Survey. Significance was assessed using two tailed independent sample t-tests and z-tests at α = 0.1. Fourteen adults and 30 caregivers of LC-FAOD patients (answering for 37 patients) answered the survey (51 unique respondents). 59.2% of LC-FAOD patients experienced effects on their schooling due to LC-FAOD. 84.2% of working patients experienced effects on their work due to LC-FAOD. 70% of caregivers experienced effects on their work due to their child's LC-FAOD. Unique respondents report that muscle weakness (69%), physical fatigue (49%), and rhabdomyolysis (39%) are the most impactful symptoms of LC-FAOD. Adults (n = 14) scored significantly below the normalized average (50) on both physical (34.51, p < 0.001) and mental (45.27, p = 0.04) component scores of the SF-12 health-related quality of life measure. LC-FAOD impart a high disease impact on patients and their caregivers. In particular, symptoms relating to energy production were rated as highly impactful and limiting. Activities that may be considered normal for many people can prove to be very difficult or impossible for respondents with LC-FAOD, with respondents reporting lower physical and mental health-related quality of life measures than the average American.

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

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