tURn the Lights on: Mitochondrial Transport‐RNAs and Cardiovascular Disease

Introduction to Mitochondrial Genome M itochondria are the organelles universally known as the cellular power plants because they generate most of the cellular energy by oxidative phosphorylation. Moreover, mitochondria are involved in many other cellular activities, such as hormones and heme synthesis, calcium ions storage, and regulation of cellular proliferation and/or differentiation. The role of mitochondrial dysfunction in cardiovascular pathophysiology, and in particular in myocardial infarction, cardiac hypertrophy, and heart failure has been extensively evaluated. Mitochondria are also the only extranuclear compartment that contains genetic material in form of deoxyribonucleic acid (DNA), probably as the result of an endosymbiotic event between ancestral eukaryotic cells and aerobic bacteria in the early evolutionary stage of eukaryotes. Each cell contains hundreds to thousands of copies of the mitochondrial DNA (mtDNA) genome, which has a maternal inheritance. Human mtDNA is a closed circular double-stranded DNA with 16 569 base pairs (bp) encoding 37 genes: 13 for the essential subunits of respiratory complexes I, III, IV, and V; 22 for mitochondrial transport-RNAs (mt-tRNAs); and 2 for ribosomal-RNAs (mt-rRNAs). All the RNA components necessary for mitochondrial translation are supplied in mitochondria, whereas all protein components are encoded by nuclear DNA and transported into the mitochondria after their cytoplasmic synthesis. The biochemical processes in mitochondria occur at much faster rates than those in the host cell. The rapidity of mtDNA replication machinery, however, is not without consequences, particularly due to the presence of reactive oxygen species (ROS) in mitochondria environment. Of consequence, mtDNA is more prone to accumulate mutations with a 16 times higher mutation accumulation rate than the nuclear DNA. Mutations could initiate a cyclic process in which impaired mitochondrial functions and increased ROS cause a higher error rates of DNA polymerases with further accumulation of mutated mtDNA. Mutations in mtDNA have been linked to various maternal inherited human diseases. A large number of mutations in mt-tRNA genes have been mapped to mt-tRNAs locus, and approximately half of mitochondrial disease is caused by mutations involving these genes (Table). Mutations in an mt-tRNA gene may negatively influence biogenesis and functioning of tRNAs after their transcription, including processing, post-transcriptional modification, aminoacylation, association with mitochondrial elongation factors, and/or interactions with the mitoribosome during translation. Mutations rarely provoke critical structural and/or functional alterations of tRNAs, because they generally result in a severe phenotype that is likely to be incompatible with embryogenesis and development. The coexistence of a mixture of molecules of mutated and wild type mtDNA within mitochondria is called heteroplasmy and the percentage of mutated, pathologic DNA is a key factor for the severity of disease; on the contrary the presence of all identical copies of mtDNA, wild type or pathologic, is known as homoplasmy.