MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria

Chatterjee, Aindrila; Seyfferth, Janine; Lucci, Jacopo; Gilsbach, Ralf; Preißl, Sebastian; Böttinger, Lena; Mårtensson, Christoph U.; Panhale, Amol; Stehlé, Thomas; Kretz, Oliver; Sahyoun, Abdullah H.; Avilov, Sergiy V.; Eimer, Stefan; Hein, Lutz; Pfanner, Nikolaus; Becker, Thomas; Akhtar, Asifa

doi:10.1016/j.cell.2016.09.052

Cited by 144 publications

(160 citation statements)

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“…These modifications include lysine methylation, phosphorylation, acetylation, ubiquitylation, sumoylation, and PARylation (reviewed in Bannister and Kouzarides, 2011). The enzymatic acetylation inside mitochondria has been recently acknowledged as four acetyl transferases ACAT1, MOF, GCN5L1, and PCAF have been identified in the mitochondria and are responsible for regulation of acetylation levels of mitochondrial proteins (Fan et al, 2014;Chatterjee et al, 2016;Wang et al, 2017;Savoia et al, 2019). It is estimated that approximately 63% of proteins that are localized within the mitochondrion contain lysine acetylation sites, and in one study conducted in 2011, 216 phosphopeptides were identified from mitochondrial preparations (Zhao et al, 2011).…”

Section: Post-translational Modifications Of Mitochondrial Nucleoid Pmentioning

confidence: 99%

Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

120

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Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. Although only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post‐translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging‐related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short noncoding RNAs, and post‐translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. Environ. Mol. Mutagen., 60:668–682, 2019. © 2019 Wiley Periodicals, Inc.

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Section: Post-translational Modifications Of Mitochondrial Nucleoid Pmentioning

confidence: 99%

Mitochondrial DNA: Epigenetics and environment

Sharma

Pasala

Prakash

2019

Environ and Mol Mutagen

120

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“…Interestingly, it was recently reported that the nuclear MYST family acetyl transferase MOF is also present in mitochondria where it binds mtDNA and regulates expression of OXPHOS genes from both, nDNA and mtDNA (Chatterjee et al , ). MOF deficiency resulted not only in mitochondrial dysfunction but also in hypertrophic cardiomyopathy and cardiac failure (Chatterjee et al , ).…”

Section: Effects Of Reactive Oxygen Species On Epigenetic Mechanismsmentioning

confidence: 99%

The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system

Kietzmann

Petry

Shvetsova

et al. 2017

British J Pharmacology

189

119

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*Authors contributed equally.Cardiovascular diseases are among the leading causes of death worldwide. Reactive oxygen species (ROS) can act as damaging molecules but also represent central hubs in cellular signalling networks. Increasing evidence indicates that ROS play an important role in the pathogenesis of cardiovascular diseases, although the underlying mechanisms and consequences of pathophysiologically elevated ROS in the cardiovascular system are still not completely resolved. More recently, alterations of the epigenetic landscape, which can affect DNA methylation, post-translational histone modifications, ATP-dependent alterations to chromatin and non-coding RNA transcripts, have been considered to be of increasing importance in the pathogenesis of cardiovascular diseases. While it has long been accepted that epigenetic changes are imprinted during development or even inherited and are not changed after reaching the lineage-specific expression profile, it becomes more and more clear that epigenetic modifications are highly dynamic. Thus, they might provide an important link between the actions of ROS and cardiovascular diseases. This review will provide an overview of the role of ROS in modulating the epigenetic landscape in the context of the cardiovascular system. This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine; 8-oxodG, 8-oxo-2 0 -deoxyguanosine; BAF, Brg1-associated factors; BER, base excision repair; BRG1, Brahma-related gene 1; BRM, Brahma; CBP, CREB binding protein; CHD, chromodomain helicase DNA-binding; CK2, casein kinase 2; CpG, 5-C-phosphate-G-3 0 ; Cys, cysteine; DNMT, DNA methyltransferase; DPF3a, double plant homeodomain (PHD) finger protein 3a; E2F1, E2F transcription factor 1; ETC, electron transport chain; EZH2, enhancer of zeste 2 PRC2 subunit; GCN5, general control nonderepressible 5; GPX1, glutathione peroxidase; HAT, histone acetyltransferases; HDAC, histone deacetylase; HDM, histone demethylase; HIF1, hypoxia-inducible factor 1; HMT, histone methyltransferases; ISWI, imitation switch; KDM, histone demethylase; LINE-1, long interspersed nuclear element-1; lncRNA, long non-coding RNA; LSD1, lysine demethylase 1A; miRNA, microRNA; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; NOX, NADPH oxidases; OGG1, 8-oxoguanine DNA glycosylase; OXPHOS, oxidative phosphorylation; PARP, poly(ADP-ribose)-polymerase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PHD, prolyl hydroxylase; PolG, polymerase γ; PPARγ, peroxisome proliferator-activated receptor gamma; PRC, polycomb repressive complex; PRMT, protein arginine N-methyltransferase; ROS, reactive oxygen species; SAM, S-adenosyl methionine; SET, Su(var)3-9, Enhancer of Zeste, Trithorax; SIRT, sirtuin; SMYD1, SET and MYND domain-containing protein 1; SNF2H, sucrose nonfermentable 2 hom...

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“…The PLA signal was localized on all chromosomes and was abundant in the cytoplasm, potentially reflecting mitochondrial MOF [7]. The ubiquitylated sites in the structured C-terminal half of the protein were qualitatively similar in male or female cells, and therefore not due to the action of the male-specific MSL2 E3 ligase.…”

Section: Discussionmentioning

confidence: 99%

“…the one that is chromosome-engaged at the X territories, and may escape detection because mass spectrometry approaches are highly biased towards abundant peptides. Conceivably, a fraction of MOF does not reside in the MSL-DCC but rather in NSL-type complexes, which regulate many promoters on all chromosomes as well as mitochondrial transcription in mammals [1,2,5,7]. MOF may be substrate of other E3 ligases (about 150 E3 ligases exist in Drosophila [36]), whose combined activities are likely to dominate ubiquitylation events in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…In context of the ‘NSL’ (non-specific-lethal) complex, the enzyme associates with many housekeeping genes, where it acetylates histone H4 of promoter nucleosomes to facilitate transcription initiation [1–6]. In mammals a variant of the NSL complex also regulates the expression of respiratory genes in mitochondria, but in this case the substrate for its acetylation is unknown [7]. …”

Section: Introductionmentioning

confidence: 99%

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Ubiquitylation of the acetyltransferase MOF in Drosophila melanogaster

et al. 2017

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The nuclear acetyltransferase MOF (KAT8 in mammals) is a subunit of at least two multi-component complexes involved in transcription regulation. In the context of complexes of the ‘Non-Specific-Lethal’ (NSL) type it controls transcription initiation of many nuclear housekeeping genes and of mitochondrial genes. While this function is conserved in metazoans, MOF has an additional, specific function in Drosophila in the context of dosage compensation. As a subunit of the male-specific-lethal dosage compensation complex (MSL-DCC) it contributes to the doubling of transcription output from the single male X chromosome by acetylating histone H4. Proper dosage compensation requires finely tuned levels of MSL-DCC and an appropriate distribution of MOF between the regulatory complexes. The amounts of DCC formed depends directly on the levels of the male-specific MSL2, which orchestrates the assembly of the DCC, including MOF recruitment. We found earlier that MSL2 is an E3 ligase that ubiquitylates most MSL proteins, including MOF, suggesting that ubiquitylation may contribute to a quality control of MOF’s overall levels and folding state as well as its partitioning between the complex entities. We now used mass spectrometry to map the lysines in MOF that are ubiquitylated by MSL2 in vitro and identified in vivo ubiquitylation sites of MOF in male and female cells. MSL2-specific ubiquitylation in vivo could not be traced due to the dominance of other, sex-independent ubiquitylation events and conceivably may be rare or transient. Expressing appropriately mutated MOF derivatives we assessed the importance of the ubiquitylated lysines for dosage compensation by monitoring DCC formation and X chromosome targeting in cultured cells, and by genetic complementation of the male-specific-lethal mof2 allele in flies. Our study provides a comprehensive analysis of MOF ubiquitylation as a reference for future studies.

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MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria

Cited by 144 publications

References 62 publications

Mitochondrial DNA: Epigenetics and environment

Mitochondrial DNA: Epigenetics and environment

The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system

Ubiquitylation of the acetyltransferase MOF in Drosophila melanogaster

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