CMTR-1 RNA methyltransferase mutations activate widespread expression of a dopaminergic neuron-specific mitochondrial complex I gene

The mitochondrial proteome is comprised of approximately 1,100 proteins,1Rath S. Sharma R. Gupta R. Ast T. Chan C. Durham T.J. Goodman R.P. Grabarek Z. Haas M.E. Hung W.H.W. et al.MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations.Nucleic Acids Res. 2021; 49: D1541-D1547https://doi.org/10.1093/nar/gkaa1011Crossref PubMed Scopus (586) Google Scholar all but 12 of which are encoded by the nuclear genome in C. elegans. The expression of nuclear-encoded mitochondrial proteins varies widely across cell lineages and metabolic states,2Pagliarini D.J. Calvo S.E. Chang B. Sheth S.A. Vafai S.B. Ong S.-E. Walford G.A. Sugiana C. Boneh A. Chen W.K. et al.A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology.Cell. 2008; 134: 112-123https://doi.org/10.1016/j.cell.2008.06.016Abstract Full Text Full Text PDF PubMed Scopus (1601) Google Scholar,3Grimsrud P.A. Carson J.J. Hebert A.S. Hubler S.L. Niemi N.M. Bailey D.J. Jochem A. Stapleton D.S. Keller M.P. Westphall M.S. et al.A Quantitative Map of the Liver Mitochondrial Phosphoproteome Reveals Posttranslational Control of Ketogenesis.Cell Metab. 2012; 16: 672-683https://doi.org/10.1016/j.cmet.2012.10.004Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar,4Kuhn K.M. DeRisi J.L. Brown P.O. Sarnow P. Global and Specific Translational Regulation in the Genomic Response of Saccharomyces cerevisiae to a Rapid Transfer from a Fermentable to a Nonfermentable Carbon Source.Mol. Cell Biol. 2001; 21: 916-927https://doi.org/10.1128/mcb.21.3.916-927.2001Crossref PubMed Scopus (0) Google Scholar but the factors that specify these programs are not known. Here, we identify mutations in two nuclear-localized mRNA processing proteins, CMTR1/CMTR-1 and SRRT/ARS2/SRRT-1, which we show act via the same mechanism to rescue the mitochondrial complex I mutant NDUFS2/gas-1(fc21). CMTR-1 is an FtsJ-family RNA methyltransferase that, in mammals, 2′-O-methylates the first nucleotide 3′ to the mRNA CAP to promote RNA stability and translation5Picard-Jean F. Brand C. Tremblay-Létourneau M. Allaire A. Beaudoin M.C. Boudreault S. Duval C. Rainville-Sirois J. Robert F. Pelletier J. et al.2'-O-methylation of the mRNA cap protects RNAs from decapping and degradation by DXO.PLoS One. 2018; 13e0193804https://doi.org/10.1371/journal.pone.0193804Crossref Scopus (45) Google Scholar,6Muthukrishnan S. Morgan M. Banerjee A.K. Shatkin A.J. Influence of 5'-terminal m7G and 2'--O-methylated residues on messenger ribonucleic acid binding to ribosomes.Biochemistry. 1976; 15: 5761-5768https://doi.org/10.1021/bi00671a012Crossref PubMed Scopus (81) Google Scholar,7Haline-Vaz T. Silva T.C.L. Zanchin N.I.T. The human interferon-regulated ISG95 protein interacts with RNA polymerase II and shows methyltransferase activity.Biochem. Biophys. Res. Commun. 2008; 372: 719-724https://doi.org/10.1016/j.bbrc.2008.05.137Crossref PubMed Scopus (31) Google Scholar,8Bélanger F. Stepinski J. Darzynkiewicz E. Pelletier J. Characterization of hMTr1, a human Cap1 2'-O-ribose methyltransferase.J. Biol. Chem. 2010; 285: 33037-33044https://doi.org/10.1074/jbc.m110.155283Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar. The mutations isolated in cmtr-1 are dominant and lie exclusively in the regulatory G-patch domain. SRRT-1 is an RNA binding partner of the nuclear cap-binding complex and determines mRNA transcript fate.9Lykke-Andersen S. Rouvière J.O. Jensen T.H. ARS2/SRRT: at the nexus of RNA polymerase II transcription, transcript maturation and quality control.Biochem Soc T. 2021; 49: 1325-1336https://doi.org/10.1042/bst20201008Crossref PubMed Scopus (0) Google Scholar We show that cmtr-1 and srrt-1 mutations activate embryonic expression of NDUFS2/nduf-2.2, a paralog of NDUFS2/gas-1 normally expressed only in dopaminergic neurons, and that nduf-2.2 is necessary for the complex I rescue by the cmtr-1 G-patch mutant. Additionally, we find that loss of the cmtr-1 G-patch domain cause ectopic localization of CMTR-1 protein to processing bodies (P bodies), phase-separated organelles involved in mRNA storage and decay.10Ivanov P. Kedersha N. Anderson P. Stress Granules and Processing Bodies in Translational Control.Csh Perspect Biol. 2019; 11a032813https://doi.org/10.1101/cshperspect.a032813Crossref Scopus (257) Google Scholar P-body localization of the G-patch mutant CMTR-1 contributes to the rescue of the hyperoxia sensitivity of the NDUFS2/gas-1 mutant. This study suggests that mRNA methylation at P bodies may control nduf-2.2 gene expression, with broader implications for how the mitochondrial proteome is translationally remodeled in the face of tissue-specific metabolic requirements and stress.