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Combination therapy for mitochondrial disorders

Study shows how one specific combination therapy may provide measurable benefits to patients with mitochondrial respiratory chain disorders.

Mitochondrial disorders

Mitochondrial respiratory chain disorders are a heterogenous yet collectively common group of energy disorders. Clinical manifestations result from the diverse aspects of the respiratory chain’s downstream cellular pathophysiology. Since researchers found the first genetic cause three decades ago, researchers have now discovered roughly 350 different genes that directly impair mitochondrial respiratory chain function. Other genetic and non-genetic conditions, medication and environmental exposures can also affect respiratory chain function.

In the absence of FDA-approved therapies, experts manage patients with a ‘mitochondrial cocktail’ of antioxidants, cofactors, and vitamin supplements. To date, there is no single, gold-standard mitochondrial cocktail composition, dosing recommendations and clinical trials supporting the safety and efficacy of administering combinatorial therapies.

Combination treatment regimens

In this study, published in Human Molecular Genetics, researchers used preclinical models – nematodes and zebrafish – to evaluate whether rationally designed mitochondrial cocktails might yield objective effects to improve survival, health and mitochondrial physiology. The team focussed their study on complex I of the respiratory chain as this is the most common biochemical site of dysfunction in mitochondrial disease.

Their previous work demonstrated that 17 different metabolic modifiers, signalling modifiers or antioxidants can significantly rescue the shortened lifespan of nematodes with respiratory chain defects. In their current work, they evaluated 11 random combinations of these treatment classes on lifespan. They found that synergistic rescue occurred in nematodes with only one combination – glucose, nicotinic acid, and N-acetylcysteine. This combination treatment yielded survival and cellular physiology improvements without exacerbating any negative side effects. Moreover, validation studies in zebrafish, showed that this combination therapy prevented stress-induced brain death. This indicates that this therapy may prevent metabolic strokes, such as those that occur in Leigh syndrome and other mitochondrial syndromes. The therapy also rescued larval activity and lactate, ATP and glutathione levels.


Overall, these findings provide preclinical evidence in two animal models of mitochondrial complex I disease to demonstrate that combinatorial therapy significantly improved animal resiliency to stressors. Further clinical trials will be important to evaluate the efficacy of this combinatorial therapy in human subjects with mitochondrial disease.

Senior study author Marni Falk expressed:

“The variable combinations of therapies used to manage mitochondrial disease patients tend to include empirically-based ‘cocktails’ of vitamins and nutrients whose safety and efficacy are difficult to objectively evaluate and compare.

Our preclinical study demonstrates that identifying the right combination of therapies that is rationally designed based on addressing the unique cellular deficiencies of major mitochondrial disease classes can provide clear, measurable survival and health benefits over individual therapies that each address only part of the cellular problem. It is important to translate these research insights into future clinical studies that test whether these optimised combinational therapy regimens improve health and provide resiliency to prevent clinical disease progression in mitochondrial disease patients.”

Image credit: By wir0man –