Deficient mitochondrial tRNA modifications arising from TRMU mutation led to the liver-specific failure

Posttranscriptional nucleotide modifications of tRNAs play the critical roles in their structure and function. Deficient τm 5 s 2 U modifications of mitochondrial tRNA Glu , tRNA Gln and tRNA Lys arising from TRMU mutations primarily manifest the liver failure. However, mechanisms of tissue specificity in TRMU-induced deficiencies remain largely elusive. In this report, we demonstrated that the loss of τm 5 s 2 U in mitochondrial tRNAs due to TRMU-deficiency caused the tissue-specific manifestation that contributed to pathogenesis of liver failures in the zebrafish. A wide range levels of τm 5 s 2 U in tRNA Lys , tRNA Glu , and tRNA Gln occurred across the zebrafish brain, muscle, eye, liver and ovum tissues. Striking differences in tissue-specific effects of conformation, stability and aminoacylation of tRNA Glu , tRNA Lys and tRNA Gln were observed among five tissues of trmu knockout (KO) zebrafish. Notably, livers are vulnerable to the loss of τm 5 s 2 U of tRNAs, evidenced by more severe failures in these tRNA metabolisms including conformation, instability and aminoacylation in liver than those in other four tissues of trmu KO zebrafish. These aberrant tRNA metabolisms altered the assembly, stability, and activities of complexes I, III and IV, especially pronounced in the liver of trmu KO zebrafish. Notably, livers displayed the highest ratios in the levels and activities of complex I to complex II in across five tissues, indicating the liver-specific electron flow preferences through complex I to coenzyme Q to complex III. These tissue-specific complex I deficiencies manifested the liver failures including hepatic steatosis and enlargement. Our findings provide new insights into the mechanism of liver-specific defects arising from the aberrant nucleotide modification of mitochondrial tRNAs.