Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation

Research output: Contribution to journalArticle

Abstract

Lysine methylation is an important and much-studied posttranslational modification of nuclear and cytosolic proteins but is present also in mitochondria. However, the responsible mitochondrial lysine-specific methyltransferases (KMTs) remain largely elusive. Here, we investigated METTL12, a mitochondrial human S-adenosylmethionine (AdoMet)-dependent methyltransferase and found it to methylate a single protein in mitochondrial extracts, identified as citrate synthase (CS). Using several in vitro and in vivo approaches, we demonstrated that METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. Moreover, METTL12 was strongly inhibited by the reaction product S-adenosylhomocysteine (AdoHcy). In summary, we have uncovered a novel human mitochondrial KMT that introduces a methyl modification into a metabolic enzyme and whose activity can be modulated by metabolic cues. Based on the established naming nomenclature for similar enzymes, we suggest that METTL12 be renamed CS-KMT (gene name CSKMT).

Details

Authors
External organisations
  • University of Oslo
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology

Keywords

  • Citrate (si)-Synthase/genetics, HeLa Cells, Humans, Methylation, Methyltransferases/classification, Mitochondrial Proteins/classification, Oxaloacetic Acid/metabolism, S-Adenosylhomocysteine/metabolism
Original languageEnglish
Pages (from-to)17950-17962
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number43
Publication statusPublished - 2017 Oct 27
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes