Lysine methylation by the mitochondrial methyltransferase FAM173B optimizes the function of mitochondrial ATP synthase.

TitleLysine methylation by the mitochondrial methyltransferase FAM173B optimizes the function of mitochondrial ATP synthase.
Publication TypeJournal Article
Year of Publication2019
AuthorsMałecki, JM, Willemen, HLDM, Pinto, R, Y Y Ho, A, Moen, A, Kjønstad, IF, Burgering, BMT, Zwartkruis, F, Eijkelkamp, N, Falnes, PØ
JournalJ Biol Chem
Volume294
Issue4
Pagination1128-1141
Date Published2019 01 25
ISSN1083-351X
KeywordsAnimals, Cell Line, Computational Biology, HeLa Cells, Histone-Lysine N-Methyltransferase, Humans, Lysine, Methylation, Mice, Mitochondria, Mitochondrial Proton-Translocating ATPases
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) 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 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 ).

DOI10.1074/jbc.RA118.005473
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.RA118.005473
PubMed ID30530489
PubMed Central IDPMC6349101