Asymmetric Arginine Dimethylation Modulates Mitochondrial Energy Metabolism and Homeostasis in Caenorhabditis elegans

Abstract

Protein arginine methyltransferase 1 (PRMT-1) catalyzes asymmetric arginine dimethylation on cellular proteins and modulates various aspects of biological processes, such as signal transduction, DNA repair, and transcriptional regulation. We have previously reported that the null mutant of prmt-1 in Caenorhabditis elegans exhibits a slightly shortened life span, but the physiological significance of PRMT-1 remains largely unclear. Here we explored the role of PRMT-1 in mitochondrial function as hinted by a two-dimensional Western blot-based proteomic study. Subcellular fractionation followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that PRMT-1 is almost entirely responsible for asymmetric arginine dimethylation on mitochondrial proteins. Importantly, isolated mitochondria from prmt-1 mutants represent compromised ATP synthesis in vitro, and wholeworm respiration in prmt-1 mutants is decreased in vivo. Transgenic rescue experiments demonstrate that PRMT-1-dependent asymmetric arginine dimethylation is required to prevent mitochondrial reactive oxygen species (ROS) production, which consequently causes the activation of the mitochondrial unfolded-protein response. Furthermore, the loss of enzymatic activity of prmt-1 induces food avoidance behavior due to mitochondrial dysfunction, but treatment with the antioxidant N-acetylcysteine significantly ameliorates this phenotype. These findings add a new layer of complexity to the posttranslational regulation of mitochondrial function and provide clues for understanding the physiological roles of PRMT-1 in multicellular organisms. KEYWORDS Caenorhabditis elegans, PRMT-1, asymmetric arginine methylation, mitochondriaA rginine methylation has drawn attention as a widespread posttranslational modification that often occurs in RNA-binding proteins, signaling molecules, DNA repair machinery, and transcriptional factors (1-5). This modification is classified according to the number and position of the methyl groups on a guanidino nitrogen of arginine residue, namely, monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), or symmetric dimethylarginine (SDMA). A family of protein arginine methyltransferases (PRMT) is responsible for catalyzing first the formation of an MMA as an intermediate, and subsequently type I enzymes, including further catalyze the generation of ADMA, while type II enzymes, including PRMT-5, PRMT-7, and FBXO11, catalyze the generation of SDMA (5). Among them, PRMT-1 is known to be the predominant type I enzyme in mammalian cells, whereas its physiological significance at the whole-body level has remained unclear due to embryonic

Protein arginine methyltransferase expression and activity during myogenesis

“…We suspected that a potential mechanism linking PRMT1 inhibition to the observed differentiation defects was mitochondrially mediated. Our rationale was based on previous studies implicating PRMT1 [ 49 , 50 ] and arginine methyltransferase activity [ 51 ] in mitochondrial biogenesis and function. Indeed, Teyssier et al [ 50 ] very elegantly demonstrated more than a decade ago that PRMT1 methylates PGC-1α, a master regulator of muscle plasticity and mitochondrial biogenesis, which directly stimulates the transcriptional function of the co-activator.…”

“…Indeed, Teyssier et al [ 50 ] very elegantly demonstrated more than a decade ago that PRMT1 methylates PGC-1α, a master regulator of muscle plasticity and mitochondrial biogenesis, which directly stimulates the transcriptional function of the co-activator. More recent work from Sha et al [ 49 ] showed that PRMT1 is almost entirely responsible for depositing the ADMA mark on mitochondrial proteins, and that PRMT1 knockdown resulted in reduced mitochondrial respiratory activity, ATP synthesis, as well as a significant elevation in oxidant production. Consistent with these reports, we observed that PRMT1 inhibition led to attenuated mitochondrial biogenesis and function in skeletal muscle cells.…”

AC. elegansgenome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function

“…It is possible that knockdown of some seemingly unrelated genes identified in our screen may result in hypersensitivity to levamisole due to reduced cellular ATP and future studies will test this hypothesis. Loss of pat-4 (Integrin Linked Kinase), tln-1 (Talin I), unc-73 (Trio), and unc-60 (Cofilin) causes fragmentation of the muscle mitochondrial network, while loss of prmt-1 (Protein Arginine Methyltransferase I) has been shown to reduce ATP synthesis ( Etheridge et al 2015 ; Sha et al 2017 ). Further, we reason that mutants with reduced ATP usage would produce a resistant phenotype.…”

Experimentally based structural model of Yih1 provides insight into its function in controlling the key translational regulator Gcn2

“…The physiological roles of protein methylation have been widely studied. Methylation is involved in signal transduction, mRNA splicing, transcriptional control, DNA repair, protein translocation, and mitochondrion energy metabolism [49,50]. Although the Yih1 used in this study is a product of heterologous expression, the observed dimethylation of Arg144 or Lys36 points to a possible mechanism that could be used by S. cerevisiae for shifting the balance between the open and closed conformations thus influencing key cellular functions.…”