Arkadiusz Kazula, Ewa Kazula

Farmakologiczne i molekularne strategie w terapii zaburzeń mitochondrialnych
2015-03-26

Pharmacological and molecular strategies in therapy of mitochondrial disorders

Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Until even only a few years ago, the idea that effective therapies for human mitochondrial disorders resulting from dysfunction of the respiratory chain/oxidative phosphorylation system (OxPhos) could be developed was unimaginable. The obstacles to treating diseases caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), and which had the potential to affect nearly every organ system, seemed overwhelming. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. Targeting reactive oxygen species has been a treatment of interest for many years; however, only in recent years has it been possible to direct antioxidant delivery specifically into the mitochondria. 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. 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. Increasing mitochondrial biogenesis, whether by pharmacological approaches, dietary manipulation or exercise therapy, is also currently an active area of research. Among these are techniques to upregulate mitochondrial biogenesis, to enhance organellar fusion and fission, to “shift heteroplasmy,” and to eliminate the burden of mutant mtDNAs via cytoplasmic transfer. Modulating the mitochondrial membrane lipid milieu have also emerged as possible treatment strategies. Recent technological advances in gene therapy, including allotopic and transkingdom gene expression and mitochondrially targeted transcription activator-like nucleases, have led to promising results in cell and animal models of mitochondrial diseases, but most of these techniques are still far from clinical application.

Keywords: mitochondrial pharmacology, mitochondrial gene therapy, oxidative phosphorylation system (OxPhos), respiratory chain (RC), enzyme replacement therapy (ERT), ketogenic diet (KD), Kearns– Sayre syndrome (KSS), Leber’s hereditary optic neuropathy (LHON), mitochondrial DNA depletion syndrome (MDDS), mitochondrial encephalomyopathy (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE), mitochondrial DNA (mtDNA), neuropathy, co=activator PGC-1 α, reactive oxygen species (ROS).

© Farm Pol, 2015, 71(3): 147-164