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 τm⁵s²U 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 τm⁵s²U 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 level of τm⁵s²U 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 KO zebrafish. Notably, livers are vulnerable to the loss of τm⁵s²U 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.