Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders.
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 beta-oxidation of fatty acids, the metabolic interactions between the two are not well defined. Defects in peroxisomal beta-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.
Holmes
R D
RD
Department of Pediatrics, William Beaumont Hospital, Royal Oak, MI 48073.
Moore
K H
KH
Ofenstein
J P
JP
Tsatsos
P
P
Kiechle
F L
FL
D000140:Acidosis, Lactic / Q000150:complications* / Q000201:enzymology; D000326:Adrenoleukodystrophy / Q000150:complications* / Q000201:enzymology; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D002950:Citrate (si)-Synthase / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D008830:Microbodies / Q000201:enzymology / Q000502:physiology*; D017240:Mitochondrial Myopathies / Q000150:complications* / Q000201:enzymology; D010084:Oxidation-Reduction; D010170:Palmitoyl-CoA Hydrolase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
D007773:Lactates; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D002374:Catalase; D002950:Citrate (si)-Synthase; D010170:Palmitoyl-CoA Hydrolase