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Review
. 2022 Apr;298(4):101791.
doi: 10.1016/j.jbc.2022.101791. Epub 2022 Mar 3.

Protein methylation in mitochondria

Jędrzej M Małecki  1 , Erna Davydova  2 , Pål Ø Falnes  3
Affiliations
Review

Protein methylation in mitochondria

Jędrzej M Małecki et al. J Biol Chem. 2022 Apr.

Abstract

Many proteins are modified by posttranslational methylation, introduced by a number of methyltransferases (MTases). Protein methylation plays important roles in modulating protein function and thus in optimizing and regulating cellular and physiological processes. Research has mainly focused on nuclear and cytosolic protein methylation, but it has been known for many years that also mitochondrial proteins are methylated. During the last decade, significant progress has been made on identifying the MTases responsible for mitochondrial protein methylation and addressing its functional significance. In particular, several novel human MTases have been uncovered that methylate lysine, arginine, histidine, and glutamine residues in various mitochondrial substrates. Several of these substrates are key components of the bioenergetics machinery, e.g., respiratory Complex I, citrate synthase, and the ATP synthase. In the present review, we report the status of the field of mitochondrial protein methylation, with a particular emphasis on recently discovered human MTases. We also discuss evolutionary aspects and functional significance of mitochondrial protein methylation and present an outlook for this emergent research field.

Keywords: ATP synthase; bioenergetics; electron transport chain; methyltransferase; mitochondria; oxidative phosphorylation; protein methylation.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1
Figure 1
Protein methylation by AdoMet-dependent methyltransferases (MTases).A, schematics of MTase-catalyzed reaction showing the methyl donor AdoMet and its demethylated counterpart AdoHcy. The transferred methyl group is shown in red. B, chemical structure of various methylated amino acid residues found in proteins. AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; MTase, methyltransferase.
Figure 2
Figure 2
Overview of mitochondrial protein MTases and their substrates. Shown are the substrates of known human mitochondrial protein MTases, as well as their submitochondrial localization and the specific residues targeted. A and B, the target site(s) of NDUFAF7 on NDUFS2 (A) and METTL9 on NDUFB3 (B) are shown on the Complex I structure (generated from pdb: 5LNK). The sequence in (B) represents the N-terminal region of bovine NDUFB3, which was demonstrated to contain methylhistidines at positions 5, 7, and 9 (47). C, the methylation site in MTRF1L targeted by HEMK1 is visualized on a model generated by AlphaFold and retrieved from UniProt (ID: AF-Q9UGC7-F1). D, the methylation sites for ETFβ-KMT in ETFβ (olive green) is found in a part interacting with MCAD (light green) (adapted from ref. (24)). CoQ, coenzyme Q; e-, electron. E, Lys-395 in citrate synthase (CS) is methylated by CS-KMT only when the enzyme is in the “open” conformation (blue), but not in “closed” conformation (red) with bound oxaloacetate (cyan) (adapted from ref. (68)). F, the c8-ring of ATP-synthase consist of eight ATPSc monomers, one of which is shown in red and magnified to visualize the methylation site (Lys-43) (adapted from ref. (84)). G, in the ANT structure, a cardiolipin molecule (CL; yellow) is bound in the vicinity of the methylation site (Lys-52) (adapted from ref. (92)). For some of the MTases, alternative names are given in parentheses. All structural visualizations were made using PyMOL Molecular Graphics System, Version 1.3 (Schrodinger, LLC). ETF, electron transfer flavoprotein; MTase, methyltransferase
Figure 3
Figure 3
Phylogenetic grouping of human mitochondrial protein MTases. An unrooted phylogenetic tree of human mitochondrial protein MTases (bold) and their closest human relatives is shown. Blue indicates members of Methyltransferase Family 16, green the inter-related ANT-KMT and ATPSc-KMT that are similar to archaeal KMTs, pink the group formed by CS-KMT and three eEF1A-specific KMTs, and beige HEMK1 and its cytosolic counterpart HEMK2/N6AMT1. First, a sequence alignment of the relevant sequences was generated using MAFFT (133), and then a tree generated and rendered using the PhyML and TREEDYN programs, respectively, both found as part of the Phylogeny.fr package (134, 135, 136). KMT, lysine specific MTase; MTase, methyltransferase.
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