Drosophila CNS OXPHOS inhibition microarray
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE96802 | GEO | 2017/03/21
SECONDARY ACCESSION(S): PRJNA379770
REPOSITORIES: GEO
Similar Datasets
Project description:Mitochondrial dysfunction causes biophysical, metabolic and signalling changes that alter homeostasis and reprogram cells. We used a Drosophila model in which TFAM is overexpressed in the nervous system with or without knock-down of the ER UPR transcription factor ATF4, to investigate the how mitochondrial dysfunction and ER stress signalling affect the transcriptome.
2019-03-14 | GSE128244 | GEO
Project description:Mitochondrial dysfunction causes biophysical, metabolic and signalling changes that alter homeostasis and reprogram cells. We used a Drosophila model in which TFAM is overexpressed in the nervous system with or without Ras/MAPK pathway inhibition, by knock-down of the ETS transcription factor pointed, to investigate the how mitochondrial dysfunction and Ras/MAPK signalling affect the transcriptome. We used microarray analysis to investigate gene expression in cases of mitochondrial dysfunction in the CNS with or without Ras/MAPK pathway inhibition by knock-down of pointed (Pnt) and anterior open (Aop).
2018-05-05 | GSE114054 | GEO
Project description:Background: Transcription control of mitochondrial metabolism is essential for cellular function. A better understanding of this process will aid the elucidation of mitochondrial disorders, in particular of the many genetically unsolved cases of oxidative phosphorylation (OXPHOS) deficiency. Yet, to date only few studies have investigated nuclear gene regulation in the context of OXPHOS deficiency. In this study, we combined RNA sequencing of human complex I-deficient patient cells across 32 conditions of perturbed mitochondrial metabolism, with a comprehensive analysis of gene expression patterns, co-expression calculations and transcription factor binding sites. Results: Our analysis shows that OXPHOS genes have a significantly higher co-expression with each other than with other genes, including mitochondrial genes. We found no evidence for complex-specific mRNA expression regulation in the tested cell types and conditions: subunits of different OXPHOS complexes are similarly (co-)expressed and regulated by a common set of transcription factors. However, we did observe significant differences between the expression of OXPHOS complex subunits compared to assembly factors, suggesting divergent transcription programs. Furthermore, complex I co-expression calculations identified 684 genes with a likely role in OXPHOS biogenesis and function. Analysis of evolutionarily conserved transcription factor binding sites in the promoters of these genes revealed almost all known OXPHOS regulators (including GABP, NRF1/2, SP1, YY1, E-box factors) and a set of six yet uncharacterized candidate transcription factors (ELK1, KLF7, SP4, EHF, ZNF143, and EL2). Conclusions: OXPHOS genes share an expression program distinct from other mitochondrial genes, indicative of targeted regulation of this mitochondrial sub-process. Within the subset of OXPHOS genes we established a difference in expression between subunits and assembly factors. Most transcription regulators of genes that co-express with complex I are well-established factors for OXPHOS biogenesis. For the remaining six factors we here suggest for the first time a link with transcription regulation in OXPHOS deficiency. RNA-SEQ of whole cell RNA in 2 control and 2 complex I deficient patient fibroblast cell lines treated with 4 compounds in duplicate, resulting in a total of 2x2x4x2=32 samples
2015-08-31 | E-GEOD-65634 | biostudies-arrayexpress
Project description:Oxidative phosphorylation (OXPHOS) and glycolysis are the two major pathways for ATP production. The reliance on each varies across tissues and cell states, and can influence susceptibility to disease. At present, the full set ofmolecular mechanisms governing the relative expression and balance of these two pathways is unknown. Here, we focus on genes whose loss leads to an increase in OXPHOS activity. Unexpectedly, this class of genes is enriched for components of the pre-mRNA splicing machinery, in particular for subunits of the U1 snRNP. Among them, we show that LUC7L2 represses OXPHOS and promotes glycolysis by multiple mechanisms, including (1) splicing of the glycolytic enzyme PFKM to suppress glycogen synthesis, (2) splicing of the cystine/glutamate antiporter SLC7A11 (xCT) to suppress glutamate oxidation, and (3) secondary repression of mitochondrial respiratory supercomplex formation. Our results connect LUC7L2 expression and, more generally, the U1 snRNP to cellular energy metabolism.
2021-04-13 | GSE157917 | GEO
Project description:Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS
| PRJNA663333 | ENA
Project description:Protein homeostasis in eukaryotic organelles and their progenitor prokaryotes is regulated by a series of ATP-dependent proteases including the caseinolytic protease complex (ClpXP). In chloroplasts, ClpXP has essential roles in organelle biogenesis and maintenance , but the significance of the plant mitochondrial ClpXP remains unknown and factors that aid coordination of nuclear and mitochondrial encoded subunits for complex assembly in mitochondria await discovery. In this study, we generated knock-out lines of the single copy mitochondrial Clp protease subunit, CLPP2, in Arabidopsis thaliana. They have higher abundance of transcripts from mitochondrial genes encoding OXPHOS protein complexes, while transcripts for nuclear genes encoding other subunits of the same complexes showed no change in transcript abundance. In contrast, the protein abundance of specific nuclear-encoded subunits in OXPHOS complexes I and V increased in knockouts, without accumulation of mitochondrial-encoded counterparts in the same complex. Protein complexes mainly or wholly encoded in the nucleus were unaffected. Analysis of protein import, assembly and function of Complex I revealed that while function was retained, protein homeostasis was disrupted through slower assembly, leading to accumulation of soluble subcomplexes of nuclear-encoded subunits after import. It is proposed that CLPP contributes to the mitochondrial protein degradation network through supporting coordination and assembly of protein complexes encoded across mitochondrial and nuclear genomes.
2019-12-13 | GSE141942 | GEO
Project description:Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.
2024-04-03 | GSE263057 | GEO
Project description:Intervening in mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. However, the exploration of targeting OXPHOS for the treatment of liver cancer is still limited, and the regulatory network involved in OXPHOS inhibition remains largely unexplored. Here, employing kinome-based CRISPR screening, we find that OXPHOS inhibitor IACS-010759 exhibits limited effect in liver cancer cells due to the function of dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Genetic inactivation or pharmacological inhibition of DYRK1A combined with OXPHOS inhibitors activates transforming growth factor β (TGFβ) signalling, which is crucial for OXPHOS inhibition-triggered cell death in liver cancer cells. Mechanistically, DYRK1A directly phosphorylates SMAD3 at Thr132, thereby suppressing the negative impact of TGFβ signalling on the transcription of the glutamine transporter solute carrier family 1 member 5 (SLC1A5). This mechanism compensates for the increased glutamine requirement (?) upon OXPHOS inhibition, leading to the resistance of liver cancer cells to OXPHOS inhibition. Finally, we validated the therapeutic efficacy of targeting OXPHOS in combination with DYRK1A inhibition in multiple liver cancer models in vivo. Our study identifies DYRK1A as a novel regulator of TGF β signalling and elucidates the regulatory mechanisms governing the response to OXPHOS inhibition in tumour cells, providing novel insights into targeting OXPHOS for liver cancer therapy.
2024-11-23 | GSE254939 | GEO
Project description:Oxidative phosphorylation (OXPHOS) complexes consist of nuclear- and mitochondrial- encoded subunits, forcing cross-compartment synchronization of gene expression to achieve mitonuclear balance. To characterize how human cells coordinate OXPHOS gene expression, we establish a mitoribosome profiling approach that resolves features of the mitochondrial translatome, including the synthesis of a four amino acid mitopeptide. Strikingly, average mitochondrial and cytoplasmic synthesis rates correspond precisely across OXPHOS complexes. Coordinated mitochondrial and cytosolic synthesis does not require rapid feedback between the two translation systems. By contrast, we find that the Leigh syndrome gene, LRPPRC, maintains correlated mitochondrial and cytosolic translatomes. Our results lead to a model of human mitonuclear balance that requires tightly balanced cross-compartment protein synthesis, representing a vulnerability for cellular proteostasis.
2021-05-30 | GSE173283 | GEO
Project description:To investigate the in vivo gene expression changes in Drosophila intestinal stem cells (ISCs) when OXPHOS is disrupted and the role of FOXO in regulating this process, we dissected midguts from 4 groups of adult flies: "esg-GAL4,tub-GAL80TS,UAS-nlsGFP/UAS-mitoXhoI;UAS-pAbp-FLAG/+ & homoplasmic mt:CoIsyn" (C group), "esg-GAL4,tub-GAL80TS,UAS-nlsGFP/UAS-mitoXhoI;UAS-pAbp-FLAG/+ & heteroplasmic mt:CoIT300I" (H group, also called M group), "esg-GAL4,tub-GAL80TS,UAS-nlsGFP/UAS-mitoXhoI;UAS-pAbp-FLAG/UAS-FOXO-IR & homoplasmic mt:CoIsyn" (FC group), "esg-GAL4,tub-GAL80TS,UAS-nlsGFP/UAS-mitoXhoI;UAS-pAbp-FLAG/UAS-FOXO-IR & heteroplasmic mt:CoIT300I" (FH group, also called FM group), ~200 midguts per group. The flies were initially obtained and maintained at 18 °C till 2 days after eclosion and were then heat-shocked at 37 ºC for 2 hours and maintained in 29 °C for 5 days. Thus, the ISCs of H and FH group flies were carrying the lethal homoplasmic mitoXhoI-resistant mt:CoIT300I mitochondrial DNAs (mtDNAs) with the wild-type mtDNAs eliminated by mitoXhoI and the OXPHOS disrupted. Meanwhile, the ISCs of C and FC group flies were still carrying wild-type-like but mitoXhoI-resistant mt:CoIsyn mtDNAs. Through the mRNA tagging method with the expressed FLAG-tagged poly(A)-binding protein (pAbp) and anti-FLAG affinity pull-down, We purified and compared mRNA transcriptome profiles (RNA-seq) of different ISCs groups in duplicates. We found about 10% of the mRNAs we detected were either up-regulated or down-regulated in the OXPHOS-disrupted (M group) ISCs compared with control (C group). The down-regulated pool included many genes involved in cell differentiation, proliferation, and growth regulation. The up-regulated pool was enriched in genes participating in various metabolic processes, including glycolysis and fatty acids synthesis. This result suggests a possible metabolic adaptation in response to the OXPHOS deficiency in M group ISCs. Importantly, knockdown of FOXO in OXPHOS-disrupted ISCs restored the expression level of more than 50% of the up- or down-regulated genes, indicating that transcriptional response to OXPHOS deficiency is partially mediated by FOXO. We also noticed that genes whose expressions were altered in OXPHOS-disrupted ISCs included many related to Notch signaling, indicating the mis-regulation of this signaling in these ISCs.
2020-07-22 | GSE137231 | GEO