The molecular pathology of pathogenic mitochondrial tRNA variants

FEBS Letters

article

Uwe Richter¹  Robert McFarland¹  Robert W. Taylor¹  Sarah J. Pickett¹ 

[1] Wellcome Centre for Mitochondrial Research, The Medical School, Newcastle University;Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki;Newcastle University Biosciences Institute, Newcastle University;Newcastle University Translational and Clinical Research Institute, Newcastle University

关键词: heteroplasmy;    m.3243A>G;    m.8344A>G;    MELAS;    MERRF;    mitochondrial disease;    mitochondrial DNA;    mitochondrial tRNA;   

DOI  :  10.1002/1873-3468.14049

来源: John Wiley & Sons Ltd.

【 摘 要 】

Mitochondrial 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 understanding the molecular pathology. In this review, we consider disease caused by the two most common pathogenic mt-tRNA variants: m.3243A>G (within MT-TL1 , encoding mt-tRNA Leu(UUR) ) and m.8344A>G (within MT-TK , encoding mt-tRNA Lys ), 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 crosstalk in the manifestation of mt-tRNA-associated disease and how research in this area not only has 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.

【 授权许可】

Unknown