Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies.
Organic acidurias or organic acidemias constitute a group of inherited disorders caused by deficient activity of specific enzymes of amino acids, carbohydrates or lipids catabolism, leading to large accumulation and excretion of one or more carboxylic (organic) acids. Affected patients usually present neurologic symptoms and abnormalities, sometimes accompanied by cardiac and skeletal muscle alterations, whose pathogenesis is poorly known. However, in recent years growing evidence has emerged indicating that mitochondrial dysfunction is directly or indirectly involved in the pathology of various organic acidemias. Mitochondrial impairment in some of these diseases are generally due to mutations in nuclear genes of the tricarboxylic acid cycle or oxidative phosphorylation, while in others it seems to result from toxic influences of the endogenous organic acids to the mitochondrion. In this minireview, we will briefly summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial homeostasis may represent a relevant pathomechanism of tissue damage in selective organic acidemias. The discussion will focus on mitochondrial alterations found in patients affected by organic acidemias and by the deleterious effects of the accumulating organic acids on mitochondrial pathways that are crucial for ATP formation and transfer. The elucidation of the mechanisms of toxicity of these acidic compounds offers new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil. mwajner@ufrgs.br
Moacir
M
Wajner
Stephen I
SI
Goodman
D000102:Acetyl-CoA C-Acyltransferase / Q000172:deficiency; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000592:Amino Acid Metabolism, Inborn Errors / Q000503:physiopathology; D000818:Animals; D056889:Barth Syndrome / Q000503:physiopathology; D001928:Brain Diseases, Metabolic / Q000503:physiopathology; D020739:Brain Diseases, Metabolic, Inborn / Q000503:physiopathology; D002264:Carboxylic Acids / Q000378:metabolism*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000503:physiopathology*; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D056693:Propionic Acidemia / Q000503:physiopathology; D011693:Purpura / Q000503:physiopathology
D002264:Carboxylic Acids; D000255:Adenosine Triphosphate; D050770:Glutaryl-CoA Dehydrogenase; D000102:Acetyl-CoA C-Acyltransferase
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