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J Biol Chem. 2019 Jan 25;294(4):1128-1141. doi: 10.1074/jbc.RA118.005473. Epub 2018 Dec 10.

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

Author information

1
From the Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway and j.m.malecki@ibv.uio.no.
2
the Laboratory of Translational Immunology (LTI) and.
3
From the Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway and.
4
Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, The Netherlands.
5
From the Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway and pal.falnes@ibv.uio.no.

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 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).

KEYWORDS:

ATP synthase; ATP synthase c-subunit; ATPSc-KMT; F1F0-ATPase; FAM173B; KMT; metabolic regulation; methyltransferase; mitochondria; mitochondrial respiratory chain complex; oxidative phosphorylation; post-translational modification (PTM); protein lysine methylation; protein methylation

PMID:
30530489
PMCID:
PMC6349101
DOI:
10.1074/jbc.RA118.005473
[Indexed for MEDLINE]

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