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MOF acetyl transferase regulates transcription and respiration in mitochondria

ABSTRACT: Histone acetylation is sensitive to metabolic cues, however interplay between histone acetyl transferases and cellular metabolism remains poorly understood. Here we report the localization of a classical nuclear HAT- MOF and members of Non-Specific Lethal complex in mitochondria. MOF regulates expression of oxidative phosphorylation (OXPHOS) genes, residing in both nuclear and mitochondrial genomes, selectively in aerobically respiring cells. Furthermore, MOF/KANSL1 depletion causes impaired mitochondrial translation and reduced respiration. MOF loss is catastrophic for tissues with high-energy consumption. In mouse hearts, Mof knockout causes hypertrophic cardiomyopathy, compromised ventricular contractility/ stroke volume and ultimately leads to cardiac failure within three weeks of birth. RNA-seq analysis of the cardiomyocytes revealed deregulation of mitochondrial nutrient metabolism and OXPHOS pathways. Consistently, electron microscopy on affected tissues revealed mitochondrial deterioration with high tissue heterogeneity, commonly observed in mitochondrial diseases. Thus, we reveal a novel function of MOF in mitochondrial homeostasis and propose MOF as a sensor connecting epigenetic regulation to metabolism.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE77784 | GEO | 2016/10/21

SECONDARY ACCESSION(S): PRJNA311550

REPOSITORIES: GEO

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MOF acetyl transferase regulates transcription and respiration in mitochondria

Project description:Histone acetylation is sensitive to metabolic cues, however interplay between histone acetyl transferases and cellular metabolism remains poorly understood. Here we report the localization of a classical nuclear HAT- MOF and members of Non-Specific Lethal complex in mitochondria. MOF regulates expression of oxidative phosphorylation (OXPHOS) genes, residing in both nuclear and mitochondrial genomes, selectively in aerobically respiring cells. Furthermore, MOF/KANSL1 depletion causes impaired mitochondrial translation and reduced respiration. MOF loss is catastrophic for tissues with high-energy consumption. In mouse hearts, Mof knockout causes hypertrophic cardiomyopathy, compromised ventricular contractility/ stroke volume and ultimately leads to cardiac failure within three weeks of birth. RNA-seq analysis of the cardiomyocytes revealed deregulation of mitochondrial nutrient metabolism and OXPHOS pathways. Consistently, electron microscopy on affected tissues revealed mitochondrial deterioration with high tissue heterogeneity, commonly observed in mitochondrial diseases. Thus, we reveal a novel function of MOF in mitochondrial homeostasis and propose MOF as a sensor connecting epigenetic regulation to metabolism. We generated mRNA-seq profile of Mof depleted HeLa cells adapted in glucose or galactose media. We also present nuclear RNA seq profile from Mof deleted cardiomyocytes.

2016-10-21 | E-GEOD-77784 | biostudies-arrayexpress

MOF-mediated histone H4 lysine 16 acetylation governs mitochondrial and ciliary functions by controlling promoter interactions (scRNA-Seq)

Project description:Histone H4 lysine 16 acetylation (H4K16Ac), governed by the histone acetyltransferase (HAT) MOF, orchestrates critical functions in gene expression regulation and chromatin interaction. In this study, we show that conditional genetic deletion of Mof but not Kansl1, the essential component of the NSL complex, causes severe defects during murine skin development. Single-cell and bulk RNA-seq, in combination with MOF ChIP-seq, reveal that numerous MOF targeted and downregulated genes are highly enriched in mitochondria and cilia. Genetic deletion of Uqcrq, an essential subunit for electron transport chain Complex III, recapitulates the defects observed in MOF cKO. Single-cell ATAC-seq reveals that MOF targeted genes are controlled prominently through promoter interactions.

2023-06-12 | GSE214440 | GEO

MOF-mediated histone H4 lysine 16 acetylation governs mitochondrial and ciliary functions by controlling promoter interactions (scATAC-Seq)

2023-06-12 | GSE214439 | GEO

MOF-mediated histone H4 lysine 16 acetylation governs mitochondrial and ciliary functions by controlling promoter interactions (RNA-Seq)

2023-06-12 | GSE214437 | GEO

MOF-mediated histone H4 lysine 16 acetylation governs mitochondrial and ciliary functions by controlling promoter interactions (ChIP-Seq)

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COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function

Project description:Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here, we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members led to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain (mtETC) complex IV (CIV) integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a CIV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopied the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains CIV activity even in the absence of MOF, suggesting an activatory role of mtETC protein acetylation. Fibroblasts from MOF syndrome patients with intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.

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Mitochondrial MOF regulates energy metabolism in heart failure by ATP5B hyperacetylation

Project description:In current study, we found that the protein level of MOF in mitochondrial was significantly increased during the course of heart failure. Overexpression of mtMOF induced cardiac hypertrophy and energy metabolism disorder, as well as heart failure. When combined with mtMOF overexpression and SIRT3 deficiency, the acetylation level in cardiomyocytes was significantly upregulated, accompanied with serious enegergy abnormal and cardiac function injury. Mitochondrial substrates of MOF was identified by using acetylated proteomic analysis. We demonstrated that mtMOF and SIRT3 exhibited damage effect by regulating the acetylation level of the common substrate ATP5B. This study clarified the acetyltransferase activity of MOF in mitochondria, providing a new theoretical basis for the acetylation regulation mode of mitochondrial proteins. In addition, we provides a new research idea for exploring the relationship between hyperacetylation and energy metabolism disorder and heart failure.

2024-12-09 | PXD044074 | Pride

MOF haploinsufficiency triggers diet-induced obesity resistance (RNA-seq)

Project description:Constant crosstalk between epigenetic regulators and metabolism homeostasis ensures that several tissues can respond and adapt to environmental cues. Decreased levels of the lysine acetyltransferase (KAT), MOF, was recently associated with cerebral development and syndromic intellectual disability. However, the consequences of having a chronic reduction of MOF levels are still unveiled. Here we characterized by FIA-MS/MS the metabolic profile of Mof heterozygous animals. We generated the profile of 8 different organs that have distinct metabolic demands. Overall, our analysis revealed that Mof heterozygous mice have impaired glucose homeostasis, fatty acids metabolism, and amino acid accumulation. When exposed ad libitum to high-fat diet those animals failed to gain fat mass, while the lean mass remains unalterable. At the molecular level, using the adipocyte model we found that Mof regulates the expression of PPARs and Slc2a4. In summary, we identified the first KAT that shows high-fat diet resistance and we propose that the chronic reduction of Mof impacts metabolic disorders.

2021-07-23 | GSE154967 | GEO

MitoExome Sequencing of Mitochondrial OXPHOS Diseases (MGH)

Project description: Human disorders of mitochondrial oxidative phosphorylation (OXPHOS) represent a devastating collection of inherited diseases. These disorders impact at least 1:5000 live births, and are characterized by multi-organ system involvement. They are characterized by remarkable locus heterogeneity, with mutations in the mtDNA as well as in over 77 nuclear genes identified to date. It is estimated that additional genes may be mutated in these disorders. To discover the genetic causes of mitochondrial OXPHOS diseases, we performed targeted, deep sequencing of the entire mitochondrial genome (mtDNA) and the coding exons of over 1000 nuclear genes encoding the mitochondrial proteome. We applied this 'MitoExome' sequencing to 124 unrelated patients with a wide range of OXPHOS disease presentations from the Massachusetts General Hospital Mitochondrial Disorders Clinic. The 2.3Mb targeted region was captured by hybrid selection and Illumina sequenced with paired 76bp reads. The total set of 1605 targeted nuclear genes included 1013 genes with strong evidence of mitochondrial localization from the MitoCarta database, 377 genes with weaker evidence of mitochondrial localization from the MitoP2 database and other sources, and 215 genes known to cause other inborn errors of metabolism. Approximately 88% of targeted bases were well-covered (>20X), with mean 200X coverage per targeted base.

| phs000339 | dbGaP

MOF haploinsufficiency triggers diet-induced obesity resistance (ChIP-seq)

Project description:Constant crosstalk between epigenetic regulators and metabolism homeostasis ensures that several tissues can respond and adapt to environmental cues. Decreased levels of the lysine acetyltransferase (KAT), MOF, was recently associated with cerebral development and syndromic intellectual disability. However, the consequences of having a chronic reduction of MOF levels are still unveiled. Here we characterized by FIA-MS/MS the metabolic profile of Mof heterozygous animals. We generated the profile of 7 different organs that have distinct metabolic demands. Overall our analysis reveled that Mof heterozygous mice have impaired glucose homeostasis, fatty acids metabolism, and amino acid accumulation. Furthermore, when exposed ad libitum to high-fat diet those animals failed to gain fat mass, while the lean mass remains unalterable. Accordingly, at the molecular level, using the adipocyte model we found that Mof regulates the expression of PPARs and Slc2a4. In summary, we identified the first KAT that shows high-fat diet resistance and we propose that the chronic reduction of Mof has a strong impact on metabolic disorders.

2021-07-23 | GSE156462 | GEO

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