The Biochemical Assessment of Mitochondrial Respiratory Chain Disorders

Abstract

Mitochondrial respiratory chain (MRC) disorders are a complex group of diseases whose diagnosis requires a multidisciplinary approach in which the biochemical investigations play an important role. Initial investigations include metabolite analysis in both blood and urine and the measurement of lactate, pyruvate and amino acid levels, as well as urine organic acids. Recently, hormone-like cytokines, such as fibroblast growth factor-21 (FGF-21), have also been used as a means of assessing evidence of MRC dysfunction, although work is still required to confirm their diagnostic utility and reliability. The assessment of evidence of oxidative stress may also be an important parameter to consider in the diagnosis of MRC function in view of its association with mitochondrial dysfunction. At present, due to the lack of reliable biomarkers available for assessing evidence of MRC dysfunction, the spectrophotometric determination of MRC enzyme activities in skeletal muscle or tissue from the disease-presenting organ is considered the 'Gold Standard' biochemical method to provide evidence of MRC dysfunction. The purpose of this review is to outline a number of biochemical methods that may provide diagnostic evidence of MRC dysfunction in patients.

Keywords: FGF21; amino acids; biomarkers; lactate; mitochondrial respiratory chain; organic acids; polarography; pyruvate; spectrophotometric enzyme assay.

Figure 1

Diagram of the mitochondrial respiratory chain (MRC) and complex V illustrating proton (H+) movement during oxidative phosphorylation. Protons as pumping into the inner mitochondrial space occurs at complexes I, III and IV and the protons pass back into the matrix at complex V. This is known as the `proton circuit` and is illustrated by the arrows in the figure. Q10: Coenzyme Q₁₀. Cyt C: Cytochrome c.

Figure 2

Substrates used in polarography to assess oxygen consumption rates illustrating their site of oxidation within the mitochondrial respiratory chain (MRC). C: cytochrome c, Q: CoQ10, TMPD: N,N,N′,N′-Tetramethyl-p-phenylenediamine.