COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA817819 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18364207_1.fastq.gz | Fastqsanger.gz | |||
| SRR18364207_2.fastq.gz | Fastqsanger.gz | |||
| SRR18364208_1.fastq.gz | Fastqsanger.gz | |||
| SRR18364208_2.fastq.gz | Fastqsanger.gz | |||
| SRR18364209_1.fastq.gz | Fastqsanger.gz |
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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.
2023-10-09 | GSE199009 | GEO
Project description:The nuclear lamina constitutes more than a structural scaffold for the nucleus and plays a crucial role in protection of genomic integrity. Here we report that the loss of the lysine acetyl-transferase (KAT) MOF leads to nuclear architecture defects during interphase including micronuclei formation. We identify Lamin A/C, a major component of the nuclear lamina, to be an acetylation target of MOF. A point mutation in Lamin A phenocopies nuclear morphology defects observed upon Mof-deletion. Through single cell DNA sequencing, we reveal that either loss of Mof or Lamin A mutation result in extensive genomic instability, including chromothripsis. Our work establishes MOF-dependent Lamin acetylation as a key regulator of nuclear architecture maintenance in mammals.
2019-08-16 | PXD008539 | Pride
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
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
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 | GSE214439 | GEO
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 | GSE214437 | GEO
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 | GSE214436 | GEO
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
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.
2016-10-21 | GSE77784 | GEO
Project description:The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (Males absent On the First) is an acetyltransferase of UHRF1 to acetylate UHRF1 at Lys670 in the pre-RING linker region whereas HDAC1 is a deacetylase of UHRF1 at the same site. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity and elimination of UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs the DNMT1 recruitment and DNA methylation. Taken together, these findings not only identify MOF as a new acetyltransferase for UHRF1 but also reveal a novel mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.
2024-03-06 | PXD040426 | Pride