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

Tek N. Lamichhane, Aneeshkumar G. Arimbasseri, Keshab Rijal, James R. Iben, Fan Yan Wei, Kazuhito Tomizawa, Richard J. Maraia

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

tRNA-isopentenyl transferases (IPTases) are highly conserved enzymes that form isopentenyl-N6-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-tRNAsSer as well as cy-tRNATyr, cy-tRNATrp, and mt-tRNATrp. 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-tRNATyr alone substantially does so. Bioinformatics indicate that cy-tRNATyr 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 hypomodificationassociated metabolic deficiency results from hypoactivity of cy-tRNA, mostly tRNATyr, 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.

Original languageEnglish
Pages (from-to)583-596
Number of pages14
JournalRNA
Volume22
Issue number4
DOIs
Publication statusPublished - Apr 1 2016
Externally publishedYes

Keywords

  • Mitochondria

ASJC Scopus subject areas

  • Molecular Biology

Fingerprint Dive into the research topics of 'Lack of tRNA-i6A modification causes mitochondrial-like metabolic deficiency in S. pombe by limiting activity of cytosolic tRNA<sup>Tyr</sup>, not mito-tRNA'. Together they form a unique fingerprint.

Cite this