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

• Published in: Human molecular genetics 2019-03, Vol.28 (6), p.928-941
• Main Authors: Seminotti, Bianca, Leipnitz, Guilhian, Karunanidhi, Anuradha, Kochersperger, Catherine, Roginskaya, Vera Y, Basu, Shrabani, Wang, Yudong, Wipf, Peter, Van Houten, Bennett, Mohsen, Al-Walid, Vockley, Jerry
• Format: Article
• Language: English
• Subjects: Acyl-CoA Dehydrogenase, Long-Chain - deficiency; Acyl-CoA Dehydrogenase, Long-Chain - metabolism; Adenosine Triphosphate - metabolism; Antioxidants - pharmacology; Apoptosis - drug effects; Cell Survival - drug effects; Congenital Bone Marrow Failure Syndromes - etiology; Congenital Bone Marrow Failure Syndromes - metabolism; Electron Transport - drug effects; Endoplasmic Reticulum - metabolism; Energy Metabolism - drug effects; Lipid Metabolism, Inborn Errors - etiology; Lipid Metabolism, Inborn Errors - metabolism; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Diseases - etiology; Mitochondrial Diseases - metabolism; Mitochondrial Dynamics - drug effects; Muscular Diseases - etiology; Muscular Diseases - metabolism; Oxidation-Reduction - drug effects; Oxygen Consumption; Reactive Oxygen Species - metabolism; Signal Transduction
• ISSN: 0964-6906; 1460-2083
• 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.