The molecular pathology of pathogenic mitochondrial tRNA variants

AbstractMitochondrial diseases are clinically and genetically heterogeneous disorders, caused by pathogenic variants in either the nuclear or mitochondrial genome. This heterogeneity is particularly striking for disease caused by variants in mitochondrial DNA ‐encoded tRNA (mt‐tRNA) genes, posing challenges for both the treatment of patients and for understanding the molecular pathology. In this review, we consider disease caused by the two most common pathogenic mt‐tRNA variants: m.3243A>G (withinMT ‐TL1, encoding mt ‐tRNALeu(UUR)) and m.8344A>G (withinMT ‐TK, encoding mt ‐tRNALys), which together account for the vast majority of all mt ‐tRNA‐related disease. We compare and contrast the clinical disease they are associated with, as well as their molecular pathologies and consider what is known about the likely molecular mechanisms of disease. Finally, we discuss the role of mitochondrial‐nuclear cross‐talk in the manifestat ion of mt‐tRNA‐associated disease and how research in this area has not only the potential to uncover molecular mechanisms responsible for the vast clinical heterogeneity associated with these variants but also pave the way to develop treatment options for these devastating diseases.
Source: FEBS Letters - Category: Biochemistry Authors: Tags: REVIEW Source Type: research