Evidence that Oxidative Disbalance and Mitochondrial Dysfunction are Involved in the Pathophysiology of Fatty Acid Oxida
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REVIEW PAPER
Evidence that Oxidative Disbalance and Mitochondrial Dysfunction are Involved in the Pathophysiology of Fatty Acid Oxidation Disorders Graziela Schmitt Ribas1 · Carmen Regla Vargas1,2 Received: 15 June 2020 / Accepted: 22 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Mitochondrial fatty acid β-oxidation disorders (FAODs) are a group of about 20 diseases which are caused by specific mutations in genes that codify proteins or enzymes involved in the fatty acid transport and mitochondrial β-oxidation. As a consequence of these inherited metabolic defects, fatty acids can not be used as an appropriate energetic source during special conditions, such as prolonged fasting, exercise or other catabolic states. Therefore, patients usually present hepatopathy, cardiomyopathy, severe skeletal myopathy and neuropathy, besides biochemical features like hypoketotic hypoglycemia, metabolic acidosis, hypotony and hyperammonemia. This set of symptoms seems to be related not only with the energy deficiency, but also with toxic effects provoked by fatty acids and carnitine derivatives accumulated in the tissues of the patients. The understanding of the mechanisms by which these metabolites provoke tissue injury in FAODs is crucial for the developmental of novel therapeutic strategies that promote increased life expectancy, as well as improved life quality for patients. In this sense, the objective of this review is to present evidence from the scientific literature on the role of oxidative damage and mitochondrial dysfunction in the pathogenesis of the most prevalent FAODs: medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. It is expected that the findings presented in this review, obtained from both animal model and patients studies, may contribute to a better comprehension of the pathophysiology of these diseases. Keywords Inborn errors of metabolism · Fatty acids · Fatty acid oxidation disorders · Mitochondrial dysfunction · Redox homoeostasis · Energy metabolism
Introduction Mitochondrial beta-oxidation of fatty acids (FAO) is a vital source of energy production, especially when cell glycogen is not available. This oxidative catabolic pathway produces acetyl-CoA from acyl-CoA esters, through sequential reactions catalyzed by FAD-dependent acyl-CoA dehydrogenases, 2-enoyl-CoA hydratases, NAD-dependent * Carmen Regla Vargas [email protected] Graziela Schmitt Ribas [email protected] 1
Departamento de Análises Clínicas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Serviço de Genética Médica, Hospital de Clíınicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035‑003, Brazil
2
l-3-hydroxyacyl-CoA dehydrogenases and 3-ketoacyl-CoA thiolases (Fig. 1). Fatty acids with short ( C4–6) and medium (C6–10) chains are able to cross directly the mitochondrial membrane, while fatty acids with m
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