Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers.

Bianca Seminotti,Anuradha Karunanidhi,Shrabani Basu,Yudong Wang,Guilhian Leipnitz,Al-Walid Mohsen,Catherine Kochersperger,Vera Y Roginskaya,Peter Wipf,Bennett Van Houten,Jerry Vockley

doi:10.1093/hmg/ddy403

Abstract

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common defect of mitochondrial long-chain fatty acid β-oxidation. Patients present with heterogeneous clinical phenotypes affecting heart, liver and skeletal muscle predominantly. The full pathophysiology of the disease is unclear and patient response to current therapeutic regimens is incomplete. To identify additional cellular alterations and explore more effective therapies, mitochondrial bioenergetics and redox homeostasis were assessed in VLCAD-deficient fibroblasts, and several protective compounds were evaluated. The results revealed cellular and tissue changes, including decreased respiratory chain (RC) function, increased reactive oxygen species (ROS) production and altered mitochondrial function and signaling pathways in a variety of VLCAD-deficient fibroblasts. The mitochondrially enriched electron and free radical scavengers JP4-039 and XJB-5-131 improved RC function and decreased ROS production significantly, suggesting that they are viable candidate compounds to further develop to treat VLCAD-deficient patients.

Highlights

Very long-chain acyl-CoA dehydrogenase (VLCAD, EC: 1.3.99.3) controls the first transformation in the fatty acid oxidation (FAO) pathway and is a key enzyme for the energy metabolism in mitochondria
We demonstrated direct impairment of global mitochondrial bioenergetics and function in fibroblasts from patients with VLCAD deficiency (VLCADD)
Regardless of mutation, VLCAD-deficient cells showed a marked decrease of mitochondrial respiratory chain (RC) function and ATP levels that tended to be exaggerated by growth in glucosefree media

Summary

Introduction

Very long-chain acyl-CoA dehydrogenase (VLCAD, EC: 1.3.99.3) controls the first transformation in the fatty acid oxidation (FAO) pathway and is a key enzyme for the energy metabolism in mitochondria Individuals deficient in this enzyme (OMIM #609575) can present with a variety of clinical symptoms and a spectrum of severity that ranges from acute life-threatening illness in the newborn period to relatively mild disease first developing late in childhood or early adulthood. The first consists of severe neonatal or early onset disease with recurrent episodes of hypoglycemia, acidosis, hepatic dysfunction and cardiomyopathy. Patients who survive their initial presentation can exhibit progressive cardiomyopathy, and have a reported 75% mortality rate in the first few years of life [2]. Patients with null mutations, leading to complete absence of VLCAD, tend to have more severe symptoms than those with some residual enzymatic activity [4]

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