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tRNA-isopentenyl transferases (IPTases) are highly conserved enzymes that form isopentenyl- N  6 -A37 (i6A37) on subsets of tRNAs, enhancing their translation activity. Nuclear-encoded IPTases modify select cytosolic (cy-) and mitochondrial (mt-) tRNAs. Mutation in human IPTase, TRIT1, causes disease phenotypes characteristic of mitochondrial translation deficiency due to mt-tRNA dysfunction. Deletion of the  Schizosaccharomyces pombe  IPTase ( tit1 -Δ) causes slow growth in glycerol, as well as in rapamycin, an inhibitor of TOR kinase that maintains metabolic homeostasis . Schizosaccharomyces pombe  IPTase modifies three different cy-tRNAs Ser  as well as cy-tRNA Tyr , cy-tRNA Trp , and mt-tRNA Trp . We show that lower ATP levels in  tit1 -Δ relative to  tit1  +  cells are also more decreased by an inhibitor of oxidative phosphorylation, indicative of mitochondrial dysfunction. Here we asked if the  tit1 -Δ phenotypes are due to hypomodification of cy-tRNA or mt-tRNA. A cytosol-specific IPTase that modifies cy-tRNA, but not mt-tRNA, fully rescues the  tit1 -Δ phenotypes. Moreover, overexpression of cy-tRNAs also rescues the phenotypes, and cy-tRNA Tyr  alone substantially does so. Bioinformatics indicate that cy-tRNA Tyr  is most limiting for codon demand in  tit1 -Δ cells and that the cytosolic mRNAs most loaded with Tyr codons encode carbon metabolilizing enzymes, many of which are known to localize to mitochondria. Thus,  S. pombe  i6A37 hypomodification-associated metabolic deficiency results from hypoactivity of cy-tRNA, mostly tRNA Tyr , and unlike human  TRIT1- deficiency does not impair mitochondrial translation due to mt-tRNA hypomodification. We discuss species-specific aspects of i6A37. Specifically relevant to mitochondria, we show that its hypermodified version, ms2i6A37 (2-methylthiolated), which occurs on certain mammalian mt-tRNAs (but not cy-tRNAs), is not found in yeast.

Lack of tRNA-i6A modification causes mitochondrial-like metabolic deficiency in <i>S. pombe</i> by limiting activity of cytosolic tRNA<sup>Tyr</sup>, not mito-tRNA

Lack of tRNA-i6A modification causes mitochondrial-like metabolic deficiency in S. pombe by limiting activity of cytosolic tRNATyr, not mito-tRNA

Lack of tRNA-i6A modification causes mitochondrial-like metabolic deficiency in S. pombe by limiting activity of cytosolic tRNA^Tyr, not mito-tRNA