Lysine methylation by the mitochondrial methyltransferase FAM173B optimizes the function of mitochondrial ATP synthase
Małecki, Je drzej M.; Willemen, Hanneke L.D.M.; Pinto, Rita; Ho, Angela Y.Y.; Moen, Anders; Kjønstad, Ingrid F.; Burgering, Boudewijn M.T.; Zwartkruis, Fried; Eijkelkamp, Niels; Falnes, Pål
(2019) Journal of Biological Chemistry, volume 294, issue 4, pp. 1128 - 1141
(Article)
Abstract
Lysine methylation is an important post-translational modification that is also present on mitochondrial proteins, but the mitochondrial lysine-specific methyltransferases (KMTs) responsible for modification are in most cases unknown. Here, we set out to determine the function of human family with sequence similarity 173 member B (FAM173B), a mitochondrial methyltransferase (MTase)
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reported to promote chronic pain. Using bioinformatics analyses and biochemical assays, we found that FAM173B contains an atypical, noncleavable mitochondrial targeting sequence responsible for its localization to mitochondria. Interestingly, CRISPR/Cas9-mediated KO of FAM173B in mammalian cells abrogated trimethylation of Lys-43 in ATP synthase c-subunit (ATPSc), a modification previously reported as ubiquitous among metazoans. ATPSc methylation was restored by complementing the KO cells with enzymatically active human FAM173B or with a putative FAM173B orthologue from the nematode Caenorhabditis elegans. Interestingly, lack of Lys-43 methylation caused aberrant incorporation of ATPSc into the ATP synthase complex and resulted in decreased ATP-generating ability of the complex, as well as decreased mitochondrial respiration. In summary, we have identified FAM173B as the long-sought KMT responsible for methylation of ATPSc, a key protein in cellular ATP production, and have demonstrated functional significance of ATPSc methylation. We suggest renaming FAM173B to ATPSc-KMT (gene name ATPSCKMT).
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Keywords: Animals, Cell Line, Computational Biology, HeLa Cells, Histone-Lysine N-Methyltransferase/deficiency, Humans, Lysine/metabolism, Methylation, Mice, Mitochondria/enzymology, Mitochondrial Proton-Translocating ATPases/metabolism, post-translational modification (PTM), mitochondrial respiratory chain complex, methyltransferase, mitochondria, protein lysine methylation, oxidative phosphorylation, ATP synthase, ATPSc-KMT, KMT, ATP synthase c-subunit, FAM173B, protein methylation, metabolic regulation, Molecular Biology, Biochemistry, Cell Biology, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology Inc.
Note: Funding Information: This work was supported by Research Council of Norway Grant FRIMEDBIO-240009 and Norwegian Cancer Society Grant 107744-PR-2007-0132. The authors declare that they have no conflicts of interest with the contents of this article. This article contains Tables S1–S4 and Figs. S1–S5. 1To whom correspondence may be addressed. Tel.: 47-91151935; E-mail: j.m.malecki@ibv.uio.no. 2 Present address: Dept. of Cancer Immunology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway. 3To whom correspondence may be addressed. Tel.: 47-91151935; E-mail: pal.falnes@ibv.uio.no. 4 The abbreviations used are: MTase, methyltransferase; 7BS, seven β-strand; AdoMet, S-adenosylmethionine; ANT, adenine nucleotide translocator; Publisher Copyright: © 2019 Małecki et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
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