Assessment of in vitro and in vivo mitochondrial function in Friedreich's ataxia and Huntington's disease.

Huntington's disease (HD) and Friedreich's ataxia (FRDA) are associated with defects of respiratory-chain enzyme activities. In the respective disorders, these can be identified in tissue samples from postmortem brain and also during life from skeletal or cardiac muscle samples. The mitochondrial abnormalities are robust and reproducible. In the case of HD, it is uncertain how these mitochondrial defects fit in the pathogenetic cascade. Studies are ongoing to identify whether the respiratory-chain defect present in the brain is expressed in skeletal muscle at the spectrophotometric level. The presence of a bioenergetic defect as identified by 31P magnetic resonance spectroscopy (MRS) suggests that in HD expression of the mutant protein can exert an influence on mitochondrial function in tissues outside the central nervous system (CNS). It would appear that frataxin deficiency has a direct effect on mitochondrial function, either through iron-sulfur cluster construction or through the generation of free radicals. The identification these bioenergetic abnormalities in these neurodegenerative disorders has opened up the prospect for the development of disease-modifying therapies directed to the biochemical abnormalities demonstrated. 31P-MRS studies have detected a deficit of in vivo oxidative phosphorylation in the skeletal muscle of FRDA and HD patients and in the myocardium of FRDA patients. In both FRDA and HD patients, a relationship between the triplet repeat expansion and the extent of in vivo energy metabolism deficit has been shown. The total safety of MRS scans makes them an ideal tool for repeated assessments to monitor disease progression as well as the effect of new therapies. This chapter describes useful methods for assessment of mitochondrial function in vitro and in vivo.