Mitochondrial disorders: disease mechanisms and therapeutic approaches.

Mitochondrial disorders are now well recognized as an important cause of genetic disease. They exhibit remarkable phenotypic, biochemical, and molecular heterogeneity, and frequently involve multiple organ systems. Their complexity partly relates to the dual expression of mitochondrial proteins by both mitochondrial and nuclear genomic DNA. Multiple copies of mitochondrial DNA (mtDNA) are present in a single human mitochondrion. Each molecule exists as a double-stranded, circular, helical structure containing 37 genes: 13 encode polypeptide subunits, whilst the remaining 24 encode 22 transfer and 2 ribosomal RNAs necessary for their synthesis. These protein subunits contribute towards four of five multimeric enzymes (so-called complex I/III/IV/V, with complex II entirely nuclear-encoded) embedded in the inner mitochondrial membrane. The enzymes catalyze a sequence of redox reactions which ultimately generates adenine triphosphate, the cellular unit of energy, during oxidative phosphorylation (OXPHOS). The remaining OXPHOS subunits (more than 70 in total), in addition to the apparatus required for their transcription, translation, post-translational modification and assembly, are nuclear-encoded. The mitochondrion's dependence on nuclear DNA extends further to include the machinery required for the maintenance, replication, and repair of mtDNA molecules, the proteins for which are synthesized in the cell cytoplasm prior to transport across mitochondrial membrane for replication. Recent advancements in DNA analysis using next generation sequencing technology have provided an unprecedented expansion in the depth of knowledge concerning both molecular mechanisms and biological pathways which underpin many mitochondrial diseases. This understanding has led to the emergence of many potential targets and treatment strategies for these disorders for which there is currently no cure. This review highlights the challenges to therapy development and clinical trial design and outlines the approaches currently being investigated to treat this diverse group of disorders.