Metabolic Outcomes of Anaplerotic Dodecanedioic Acid Supplementation in Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficient Fibroblasts.

Igor Radzikh,Ryan Pearce,Erica Fatica,Rohan Shah,Yana I Sandlers,Jillian Kodger

doi:10.3390/metabo11080538

Abstract

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM 609575) is associated with energy deficiency and mitochondrial dysfunction and may lead to rhabdomyolysis and cardiomyopathy. Under physiological conditions, there is a fine balance between the utilization of different carbon nutrients to maintain the Krebs cycle. The maintenance of steady pools of Krebs cycle intermediates is critical formitochondrial energy homeostasis especially in high-energy demanding organs such as muscle and heart. Even-chain dicarboxylic acids are established as alternative energy carbon sources that replenish the Krebs cycle by bypassing a defective β-oxidation pathway. Despite this, even-chain dicarboxylic acids are eliminated in the urine of VLCAD-affected individuals. In this study, we explore dodecanedioic acid (C12; DODA) supplementation and investigate its metabolic effect on Krebs cycle intermediates, glucose uptake, and acylcarnitine profiles in VLCAD-deficient fibroblasts. Our findings indicate that DODA supplementation replenishes the Krebs cycle by increasing the succinate pool, attenuates glycolytic flux, and reduces levels of toxic very long-chain acylcarnitines.

Highlights

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM 609575) is manifested by a wide range of clinical phenotypes including hypertrophic and dilated cardiomyopathy, rhabdomyolysis, myopathy, and hypoglycemia [1,2,3,4]
In the time period Metabolites 2021, 11, x FOR PEER REVoIfEWsixteen hours and the presence of other competing carbon substrates such as 5 mM glucose and 0.2 mM palmitic acid-BSA, we observed a decrease of DODA in culture media by 22.3% and 20.0% in control and VLCAD-deficient fibroblasts, respectively (Figure 2)
The disorder is screened as a part of the newborn screening (NBS) program based on dried blood spot acylcarnitine profiles with a follow-up second-tier testing such as urine organic acids and molecular confirmatory tests

Summary

Introduction

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM 609575) is manifested by a wide range of clinical phenotypes including hypertrophic and dilated cardiomyopathy, rhabdomyolysis, myopathy, and hypoglycemia [1,2,3,4]. Some of these symptoms can be ameliorated by nutritional restrictions. To target impaired mitochondrial bioenergetics in VLCADD, anaplerotic therapy was proposed as a new treatment strategy [12,13] This therapeutic approach is directed towards the restoration of energy production by replenishing pools of Krebs cycle intermediates [14] while bypassing defective β-oxidation of long-chain fatty acids (LCFA).

Methods

Results

Conclusion