Personalized Medicine in Mitochondrial Health and Disease: Molecular Basis of Therapeutic Approaches Based on Nutritional Supplements and Their Analogs

Abstract: Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite thegreat variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerativephenotype is observed, and no specific therapy exists for a complete recovery from the disease. Themost used treatments are symptomatic and based on the administration of antioxidant cocktailscombined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement. Nevertheless, the real utility of antioxidant cocktail treatments for patients affected by MDsstill needs to be scientifically demonstrated. Unfortunately, clinical trials for antioxidant therapiesusing ?-tocopherol, ascorbate, glutathione, riboflavin, niacin, acetyl-carnitine and coenzyme Q havemet a limited success. Indeed, it would be expected that the employed antioxidants can only beeffective if they are able to target the specific mechanism, i.e., involving the central and peripheralnervous system, responsible for the clinical manifestations of the disease. Noteworthily, very oftenthe phenotypes characterizing MD patients are associated with mutations in proteins whose functiondoes not depend on specific cofactors. Conversely, the administration of the antioxidant cocktailsmight determine the suppression of endogenous oxidants resulting in deleterious effects on cellviability and/or toxicity for patients. In order to avoid toxicity effects and before administeringthe antioxidant therapy, it might be useful to ascertain the blood serum levels of antioxidants andcofactors to be administered in MD patients. It would be also worthwhile to check the localizationof mutations affecting proteins whose function should depend (less or more directly) on the cofactors to be administered, for estimating the real need and predicting the success of the proposedcofactor/antioxidant-based therapy