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Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders
Author(s) -
Holmes R. D.,
Moore K. H.,
Ofenstein J. P.,
Tsatsos P.,
Kiechle F. L.
Publication year - 1993
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/bf00710284
Subject(s) - peroxisome , endocrinology , biology , medicine , mitochondrion , peroxisomal disorder , zellweger syndrome , oxidative phosphorylation , lactic acidosis , respiratory chain , biochemistry , beta oxidation , mitochondrial myopathy , metabolism , mitochondrial dna , receptor , gene
Summary Mitochondrial myopathies and defects in oxidative phosphorylation have been described in some patients with peroxisomal disorders. Although peroxisomes and mitochondria play a role in the β‐oxidation of fatty acids, the metabolic interactions between the two are not well defined. Defects in peroxisomal β‐oxidation are associated with extracellular accumulation of very long‐chain fatty acids and may be accompanied by alterations in the intracellular pool of fatty acyl‐CoAs, which are known to alter mitochondrial function. This study was initiated to examine alterations in the intracellular pool of acyl‐CoAs and mitochondrial function in two children with generalized disorders of peroxisomal function and clinical lactic/pyruvic acidaemia. Fibroblasts were cultured from skin biopsies obtained from one child with neonatal adrenoleukodystrophy (NALD) and another with rhizomelic chondrodysplasia punctata (RCDP). Fibroblast lactate oxidation was significantly inhibited in NALD by 76% and RCDP by 92% compared to control values of 1.9±0.1 nmol/min per mg protein. Pyruvate dehydrogenase (PDH) (mean±SEM; activity nmol/min per mg protein) was: NALD 0.55±0.02 ( p <0.01), RCDP 0.44±0.02 ( p <0.01), and controls 0.83±0.02. The acid‐insoluble (long‐chain and very long‐chain) acyl‐CoA levels (mean±SEM; pmol/mg protein) were: NALD 129±69 ( p <0.01), RCDP 65±15 ( p <0.05), and control 45±7. These two patients with generalized peroxisomal disorders exhibited an increase in intracellular acyl‐CoA species accompanied by decreased PDH activity and clinical lactic/pyruvic acidaemia.