Assessment of mitochondrial respiratory chain function in hyperphenylalaninaemia

Area of Science:

• Biochemistry
• Neuroscience
• Genetics

Background:

• Phenylketonuria (PKU) is an inherited metabolic disorder.
• Untreated PKU leads to severe neurological and intellectual deficits.
• Residual neurological impairment, like tremor, occurs even in treated PKU patients.

Purpose of the Study:

• To investigate the proposed mechanism of phenylalanine (Phe) toxicity on mitochondrial respiratory chain (MRC) complex I activity and coenzyme Q(10) (CoQ(10)) biosynthesis in PKU.
• To determine if hyperphenylalaninaemia contributes to PKU pathophysiology by impairing brain energy metabolism.

Main Methods:

• Compared plasma Phe and mononuclear CoQ(10) levels in PKU patients with and without tremor.
• Exposed human astrocytoma cells to varying Phe concentrations (300–900 µmol/L) for 96 hours.
• Measured MRC complex I activity, citrate synthase activity, and CoQ(10) levels in cell cultures.

Main Results:

• No significant differences in Phe or CoQ(10) levels were observed between PKU patients with and without tremor.
• Hyperphenylalaninaemia did not significantly reduce MRC complex I activity or CoQ(10) biosynthesis in cell cultures.
• Normalized complex I and CoQ(10) levels to citrate synthase to account for mitochondrial content, yielding similar results.

Conclusions:

• The study suggests that hyperphenylalaninaemia does not impair mitochondrial respiratory chain complex I activity or CoQ(10) biosynthesis.
• These findings indicate that reduced MRC complex I activity and/or CoQ(10) biosynthesis are unlikely mechanisms underlying PKU's neurological pathology.