The molecular pathology of pathogenic mitochondrial tRNA variants.

Uwe Richter,Robert W Taylor,Sarah J Pickett,Robert Mcfarland

doi:10.1002/1873-3468.14049

Abstract

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‐tRNALeu(UUR)) and m.8344A>G (within MT‐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 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.

Highlights

Mitochondrial diseases are clinically and genetically heterogeneous disorders, caused by pathogenic variants in either the nuclear or mitochondrial genome. This heterogeneity is striking for disease caused by variants in mitochondrial DNA-encoded tRNA genes, posing challenges for both the treatment of patients and understanding the molecular pathology
The dual genetic origin of mitochondrial ribosomes and the respiratory chain imposes a unique challenge for human cells, the need to tightly coordinate the expression of the Abbreviations MELAS, encephalopathy and stroke-like episodes; MERRF, myoclonic epilepsy associated with ragged-red fibres; mito-nuclear, mitochondrial to nuclear; mt-aaRSs, mitochondrial aminoacyl-tRNA synthetases; mitochondrial DNA-encoded tRNA (mt-tRNA), mitochondrial tRNA; OXPHOS, oxidative phosphorylation
FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

Summary

Edited by Peter Rehling

Mitochondrial diseases are clinically and genetically heterogeneous disorders, caused by pathogenic variants in either the nuclear or mitochondrial genome. The overwhelming majority of mitochondrial proteins are encoded by the nuclear genome [1], but the mtDNA encodes 13 polypeptides, each of which forms a core subunit in one of the OXPHOS complexes, with the exception of complex II, which is entirely nuclear-encoded (Fig. 1A) [2,3]. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

Pathogenic mitochondrial tRNA variants

Variability in disease burden and progression

Segregation and clonal expansion

Molecular mechanisms

Findings

Future directions