Next generation sequencing in the identification of new pathogenic mechanisms for mitochondrial disorders

Henna Tyynismaa1,*

1Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland

Mitochondria are at the centre of cellular energy metabolism. They are the major site for cellular ATP generation, accomplished by the oxidative phosphorylation system (OXPHOS). The OXPHOS complexes depend on dual genetic control - thirteen protein subunits of the complexes are encoded by the mitochondrial genome (mtDNA) and synthesized by the mitochondrial translation machinery and the rest of the subunits are nuclear-encoded, synthesized in cytoplasm and imported into mitochondria. Besides the OXPHOS complex assembly, co-operation between the imported nuclear-encoded proteins and the intrinsic mitochondrial components are required in multiple levels: mtDNA expression is fully controlled by nuclear-encoded replication and transcription machinery, the mitoribosome is composed of mtDNA-encoded rRNAs and nuclear-encoded protein subunits, and the aminoacylation of mtDNA-encoded tRNAs is performed by nuclear-encoded (but mostly mitochondria-specific) set of aminoacyl-tRNA synthetases. In addition, hundreds of other imported proteins function in different metabolic pathways in the mitochondria.

During the last twenty years, mitochondrial OXPHOS disorders have been recognized as a major group of inherited diseases and mitochondrial dysfunction has been associated to neurodegerative diseases, obesity, diabetes, cancer and aging. Because of the requirement of both nuclear and mtDNA genes for OXPHOS function, mitochondrial diseases can have maternal or autosomal inheritance. Commonly in mitochondrial disorders the skeletal muscle and the central nervous system with substantial requirement of ATP are suffering the most but in fact nearly any tissue can be affected.

Next-generation sequencing methods have revolutionized the nuclear disease gene discovery in mitochondrial disorders. In particular, defects of the mitochondrial protein synthesis have emerged as a new group of mitochondrial diseases, with highly tissue-specific phenotypes.

Keywords: DNA, Inborn error of metabolism