Mitochondrial diseases therapy

Since mitochondria are essential to cell health, mitochondrial diseases tend to be severe but, thankfully, relatively uncommon. Accordingly, the medicinal chemistry of mitochondrial disorders is still in its infancy. There are no truly effective drug therapies for mitochondrial disorders, but several agents have been reported to be of some benefit in some individuals. These agents include ubiquinone (coenzyme QIO), carnitine, and riboflavin. These compounds may assist the ailing mitochondria to better complete their metabolic tasks. However, mitochondrial medicinal chemistry is an area of research in need of additional attention. 

In this chapter we review the defects of respiratory function and DNA mutations in the mitochondrial genome and nuclear DNA underlying mitochondrial diseases and discuss the roles that oxidative stress, oxidative damage, and apoptosis may play in the pathogenesis of this group of overt metabolic disorders. The cell cultures and animal models for studies of mitochondrial diseases and potential therapies are also discussed. 

Treatment of most patients with genetic mitochondrial diseases has been disappointing and has usually been approached in a sporadic, uncontrolled manner. There is no proven therapy for patients with PDC deficiency. Current strategies rely on nutritional or pharmacological interventions or both to improve patient quality of life. Recent studies have also begun to address the potential role of gene transfer for Ela defects. 

Tamopolsky, M., Practical issues in the design of studies evaluating therapy in mitochondrial diseases, MitoMatters, 1,3,2002. 

Mitsui, T., Umaki, Y., Nagasawa, M., Akaike, M., Aki, K., Azuma, H., Ozaki, S., Odomi, M., and Matsumoto, T., Mitochondrial damage in patients with long-term corticosteroid therapy development of oculoskeletal symptoms similar to mitochondrial disease, Acta Neuropathoi,... 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

Since the tragic human exposure to diethyltin salts for the therapy of an infectious skin disease by Staphylococcus in France in the 1950s, the toxic and biochemical effects of many of these derivatives have been explored. Di- and tri-ethyltin salts have been demonstrated to have pronounced effects on intermediary metabolism in brain and liver. These effects have been suggested to be due to inhibition of the mitochondrial functions9,27. 

Mitochondria are the ATP suppliers of the cells and have an important role in modulating intracellular calcium levels and cellular apoptosis. The mitochondrial respiratory chain is furthermore an important suppher of damaging free radicals. Evidence increases that mitochondria are heavily involved in numerous diseases and therefore they may become important targets for the development of new drugs and therapies [47]. 

Metabolic disturbances are frequent in patients with HIV infection and represent a multifactorial condition related both to the underlying disease and to the antiviral treatment. HIV infection itself appears to cause hyperlipidemia and insulin resistance in some patients. Protease inhibitor therapy is a major contributor to fat accumulation, hyperlipidemia, and insulin resistance. NNRTIs contribute mainly through augmentation of lipid concentrations and NRTIs to the development of lipid-associated toxicity. NRTIs can cause mitochondrial dysfunction. 

Because many of these factors are external (not produced within our own cells by mitochondrial leakage) they are more responsive to antioxidant therapies than is mitochondrial ageing, which cannot be easily reversed. This is why a healthy diet, or possibly antioxidant supplements, can postpone the onset or progression of heart disease, but do not ultimately prevent ageing. 

Bravi, D., Anderson, J.J., Dagani, F., Davis, T.L., Ferrari, R., Gillespie, M. and Chase, T.N. (1992) Effect of aging and dopaminomimetic therapy on mitochondrial respiratory function in Parkinson s disease. Mov. Disord. 1 228-231. 

An important target for gene therapy is the mitochondrial genome, mutations of which may be involved in many rare diseases. Such mitochondiiopathies may be amenable to treat-ment by genetic modifications... 

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