RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis.

Abstract:

:Post-transcriptional RNA modifications play a critical role in the pathogenesis of human mitochondrial disorders, but the mechanisms by which specific modifications affect mitochondrial protein synthesis remain poorly understood. Here we used a quantitative RNA sequencing approach to investigate, at nucleotide resolution, the stoichiometry and methyl modifications of the entire mitochondrial tRNA pool, and establish the relevance to human disease. We discovered that a N1-methyladenosine (m1A) modification is missing at position 58 in the mitochondrial tRNALys of patients with the mitochondrial DNA mutation m.8344 A > G associated with MERRF (myoclonus epilepsy, ragged-red fibers). By restoring the modification on the mitochondrial tRNALys, we demonstrated the importance of the m1A58 to translation elongation and the stability of selected nascent chains. Our data indicates regulation of post-transcriptional modifications on mitochondrial tRNAs is finely tuned for the control of mitochondrial gene expression. Collectively, our findings provide novel insight into the regulation of mitochondrial tRNAs and reveal greater complexity to the molecular pathogenesis of MERRF.

journal_name

Nat Commun

journal_title

Nature communications

authors

Richter U,Evans ME,Clark WC,Marttinen P,Shoubridge EA,Suomalainen A,Wredenberg A,Wedell A,Pan T,Battersby BJ

doi

10.1038/s41467-018-06471-z

subject

Has Abstract

pub_date

2018-09-27 00:00:00

pages

3966

issue

1

issn

2041-1723

pii

10.1038/s41467-018-06471-z

journal_volume

9

pub_type

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