Lactic acidosis and mitochondrial dysfunction in two children with peroxisomal disorders

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic Disorders

Background:

• Peroxisomal disorders are linked to mitochondrial dysfunction and defects in oxidative phosphorylation.
• Peroxisomes and mitochondria are involved in fatty acid beta-oxidation, but their metabolic interplay is not fully understood.
• Peroxisomal beta-oxidation defects cause very long-chain fatty acid accumulation, potentially affecting mitochondrial function via altered fatty acyl-CoA pools.

Observation:

• Two children with generalized peroxisomal disorders (neonatal adrenoleukodystrophy and rhizomelic chondrodysplasia punctata) presented with lactic/pyruvic academia.
• Fibroblast cultures from these patients showed significantly inhibited lactate oxidation.
• Intracellular levels of acid-insoluble (long-chain and very long-chain) acyl-CoAs were elevated in both patients compared to controls.

Findings:

• Patients with generalized peroxisomal disorders exhibited increased intracellular acyl-CoA species.
• Pyruvate dehydrogenase (PDH) activity was significantly decreased in fibroblasts from both NALD and RCDP patients.
• The observed metabolic alterations correlated with clinical lactic/pyruvic academia.

Implications:

• This study demonstrates a direct link between peroxisomal beta-oxidation defects and impaired mitochondrial function in patients.
• Elevated intracellular acyl-CoAs in peroxisomal disorders contribute to mitochondrial dysfunction and lactic acidosis.
• Understanding these metabolic interactions is crucial for diagnosing and managing peroxisomal disorders and associated metabolic complications.