Elongator-dependent modification of cytoplasmic tRNALysUUU is required for mitochondrial function under stress conditions

Marco Tigano, Roberta Ruotolo, Cristina Dallabona, Flavia Fontanesi, Antoni Barrientos, Claudia Donnini, Simone Ottonello

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

To gain a wider view of the pathways that regulate mitochondrial function, we combined the effect of heat stress on respiratory capacity with the discovery potential of a genome-wide screen in Saccharomyces cerevisiae. We identified 105 new genes whose deletion impairs respiratory growth at 37°C by interfering with processes such as transcriptional regulation, ubiquitination and cytosolic tRNA wobble uridine modification via 5-methoxycarbonylmethyl- 2-thiouridine formation. The latter process, specifically required for efficient decoding of AA-ending codons under stress conditions, was covered by multiple genes belonging to the Elongator (e.g. ELP3) and urmylation (e.g., NCS6) pathways. ELP3 or NCS6 deletants had impaired mitochondrial protein synthesis. Their respiratory deficiency was selectively rescued by overexpression of tRNALys UUU as well by overexpression of genes (BCK1 and HFM1) with a strong bias for the AAA codon read by this tRNA. These data extend the mitochondrial regulome, demonstrate that heat stress can impair respiration by disturbing cytoplasmic translation of proteins critically involved in mitochondrial function and document, for the first time, the involvement in such process of the Elongator and urmylation pathways. Given the conservation of these pathways, the present findings may pave the way to a better understanding of the human mitochondrial regulome in health and disease.

Original languageEnglish (US)
Pages (from-to)8368-8380
Number of pages13
JournalNucleic acids research
Volume43
Issue number17
DOIs
StatePublished - Sep 30 2015

ASJC Scopus subject areas

  • Genetics

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