Mitochondrial Diseases: Therapeutic Approaches

Abstract

Therapy of mitochondrial encephalomyopathies (defined restrictively as defects of the mitochondrial respiratory chain) is woefully inadequate, despite great progress in our understanding of the molecular bases of these disorders. In this review, we consider sequentially several different therapeutic approaches. Palliative therapy is dictated by good medical practice and includes anticonvulsant medication, control of endocrine dysfunction, and surgical procedures. Removal of noxious metabolites is centered on combating lactic acidosis, but extends to other metabolites. Attempts to bypass blocks in the respiratory chain by administration of electron acceptors have not been successful, but this may be amenable to genetic engineering. Administration of metabolites and cofactors is the mainstay of real-life therapy and is especially important in disorders due to primary deficiencies of specific compounds, such as carnitine or coenzyme Q10. There is increasing interest in the administration of reactive oxygen species scavengers both in primary mitochondrial diseases and in neurodegenerative diseases directly or indirectly related to mitochondrial dysfunction. Aerobic exercise and physical therapy prevent or correct deconditioning and improve exercise tolerance in patients with mitochondrial myopathies due to mitochondrial DNA (mtDNA) mutations. Gene therapy is a challenge because of polyplasmy and heteroplasmy, but interesting experimental approaches are being pursued and include, for example, decreasing the ratio of mutant to wild-type mitochondrial genomes (gene shifting), converting mutated mtDNA genes into normal nuclear DNA genes (allotopic expression), importing cognate genes from other species, or correcting mtDNA mutations with specific restriction endonucleases. Germline therapy raises ethical problems but is being considered for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is becoming increasingly important for nuclear DNA-related disorders. Progress in each of these approaches provides some glimmer of hope for the future, although much work remains to be done.

Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

“…6 The main causes of mitochondrial dysfunction are mutations of mitochondrial DNA 3 and interruption of the homeostatic loop between mitochondria and the reactive oxygen species generated by mitochondrial respiratory chain activity. 7 Supporting the strategy that mitochondrial dysfunction may be protected/reversed by drugs capable of regulating and improving mitochondrial processes, 8 we suggested that mildronate, a drug of aza-butyrobetaine class, may target mitochondria. This suggestion is based on previous data showing that mildronate is capable of protecting mitochondrial membranes from damage by free fatty acids (FFAs), 9 as well as from AZT-induced morphological changes and activation of nuclear factor kBp65 in mice cardiac tissue.…”

Ingestion of Synthetic Street Drug “25-I” (25I-NBOMe) Causing Type B Lactic Acidosis and Multi-Organ Dysfunction

“…We used a cocktail of vitamins and co-factors based on established treatments of mitochondrial disorders associated with lactic acidosis [9,10]. Thiamine, vitamin B1, is a co-factor in multiple steps in amino acid and carbohydrate metabolism, including the conversion of pyruvate to acetylCoA.…”

“…Free-radical mediated injury may occur as a consequence of mitochondrial dysfunction [10]. To mitigate this, we treated with the free-radical scavenger NAC, using dosing standards for acetaminophen-associated liver injury.…”

How Can We Treat Mitochondrial Encephalomyopathies? Approaches to Therapy

“…This often involves multiple disciplines: both physicians (neurologists, cardiologists, diabetologists, and ophthalmologists) and specialist nurses, physiotherapists, and speech therapists, depending on the clinical phenotype. 4 Although huge advances have been made over the last decade in relation to the function and structure of mitochondria and subsequently the pathogenic mechanisms underlying mitochondrial disease, there is currently no definitive pharmacological treatment for patients with mitochondrial dysfunction, 5 except for patients with primary deficiency of coenzyme Q10. Nonpharmacological treatments are increasingly being investigated, including ketogenic diet, exercise, and gene therapy.…”

“…Nonpharmacological treatments are increasingly being investigated, including ketogenic diet, exercise, and gene therapy. 4 Management is aimed primarily at minimizing disability, preventing complications, and providing prognostic information and genetic counseling based on current best practice. 6 -9 …”