Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease

Abstract

The human mitochondrial genome (mtDNA) encodes 22 tRNAs (mt-tRNAs) that are necessary for the intraorganellar translation of the 13 mtDNA-encoded subunits of the mitochondrial respiratory chain complexes. Maturation of mt-tRNAs involves 5' and 3' nucleolytic excision from precursor RNAs, as well as extensive post-transcriptional modifications. Recent data suggest that over 7% of all mt-tRNA residues in mammals undergo post-transcriptional modification, with over 30 different modified mt-tRNA positions so far described. These processing and modification steps are necessary for proper mt-tRNA function, and are performed by dedicated, nuclear-encoded enzymes. Recent growing evidence suggests that mutations in these nuclear genes (nDNA), leading to incorrect maturation of mt-tRNAs, are a cause of human mitochondrial disease. Furthermore, mtDNA mutations in mt-tRNA genes, which may also affect mt-tRNA function, processing, and modification, are also frequently associated with human disease. In theory, all pathogenic mt-tRNA variants should be expected to affect only a single process, which is mitochondrial translation, albeit to various extents. However, the clinical manifestations of mitochondrial disorders linked to mutations in mt-tRNAs are extremely heterogeneous, ranging from defects of a single tissue to complex multisystem disorders. This review focuses on the current knowledge of nDNA coding for proteins involved in mt-tRNA maturation that have been linked to human mitochondrial pathologies. We further discuss the possibility that tissue specific regulation of mt-tRNA modifying enzymes could play an important role in the clinical heterogeneity observed for mitochondrial diseases caused by mutations in mt-tRNA genes.

Keywords: RNA modification; RNA processing; mitochondria; mitochondrial disease; post-transcriptional regulation; tRNA.

FIGURE 1

Mitochondrial tRNA maturation and factors involved. Key protein factors involved in post-transcriptional nucleolytic processing and in chemical modifications of mitochondrial tRNAs. Factors associated with human disease are indicated in red; other factors characterized thus far are in blue. Note: PNPase can be either directly or indirectly involved in mt-tRNA processing (red question mark). The bacterial homologs of MTO1 and GTPBP3 form a complex, however, the interaction between the human proteins has not been shown (question mark).

FIGURE 2

Chemical modifications of mitochondrial tRNA. Schematics of the “clover leaf" secondary structure of a generic mitochondrial tRNA indicating post-transcriptionally modified bases (circles). The details of the chemical modification and enzyme responsible (if known) for each tRNA position is given in boxes, indicating a tRNA base position number next to each box. The chemical modifications identified in mammalian species other than human are in brackets. Color coding: red, enzyme responsible for the modification has been associated with human disease; blue, enzyme responsible for particular modification has been identified; gray, modifying enzyme has not been identified.

FIGURE 3

Mitochondrial tRNA metabolism and tissue specificity of associated disease. Several properties that relate to tissue-specific regulation of mitochondrial tRNA biology by nuclearly- (green) and mitochondrially encoded genes (red) are listed to the left. Possible genetic defect leading to perturbations of mitochondrial tRNA metabolism resulting from mutations in the nuclear (nDNA) or mitochondrial genome (mtDNA) are shown in the center. The tissue specific regulation of the mt-tRNA maturation pathways in conjunction with nDNA or mtDNA mutations can give rise to the cell type-specific molecular phenotypes listed to the right.