Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase
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ABSTRACT:
PROVIDER: PRJNA719212 | ENA |
REPOSITORIES: ENA
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Project description:Cancer cells have long been recognized to exhibit unique bioenergetic requirements. The apoptolidin family of glycomacrolides are distinguished by their selective cytotoxicity towards oncogene transformed cells, yet their molecular mechanism remains uncertain. We used photoaffinity analogs of the apoptolidins to identify the F1 subcomplex of mitochondrial ATP synthase as the target of apoptolidin A. CryoEM of apoptolidin and ammocidin-ATP synthase complexes revealed a novel shared mode of inhibition that was confirmed by deep mutational scanning of the binding interface to reveal resistance mutations which were confirmed using CRISPR-Cas9. Ammocidin A was found to suppress leukemia progression in vivo at doses that were tolerated with minimal toxicity. These studies reveal that OXPHOS dependent cancers are vulnerable to ATP synthase inhibition by apoptolidin family glycomacrolides compounds.
2021-05-31 | GSE171362 | GEO
Project description:The goal of this analysis was to profile the gene expression signatures associated to different neuronal doses of IF1. The mitochondrial ATP synthase produces ATP by oxidative phosphorylation and integrates different signals to regulate cellular functions and fate. The ATPase inhibitory factor 1 (IF1) is a structurally-disordered protein that inhibits the ATP synthase, contributing to metabolic reprogramming and signalling through mitochondrial reactive oxygen species (mtROS). mtROS regulate kinases and transcription factors in mitohormetic responses that favour adaptation to toxic insults. IF1 is tissue-specifically expressed and in human and mouse brain is in molar excess over the ATP synthase. Herein, we have used genetic approaches to ablate or overexpress IF1 in neurons to investigate its role in brain functions. IF1 inhibits a fraction of the ATP synthase under physiological conditions and regulates respiration, mtROS production and mitochondrial structure. Transcriptomic, proteomic and metabolomic analyses indicate that IF1 regulates synaptic transmission and cognition. Ablation of IF1 impairs short-term memory whereas IF1 overexpression increases basal synaptic transmission and learning by mtROS-dependent activation of the extracellular signal-regulated kinases 1/2 (ERK 1/2). Overall, we show that IF1 dose plays a fundamental role in the regulation of neuronal function by controlling the fraction of inhibited ATP synthase that acts as source of mitohormetic mtROS, further emphasizing the ATP synthase/IF1 as promising targets to treat cognitive disorders.
2021-05-24 | GSE154064 | GEO
Project description:Defects of mitochondrial functions lead in humans to vast array of usually multisystemic pathologies and several hundreds of diseases resulting from various defects of mitochondria biogenesis and maintenance, defects of respiratory chain complexes (OXPHOS) or defects of individual mitochondrial proteins are known. We used Agilent Whole Human Genome Microarray for gene expression profiling of genetically heterogeneous group of 13 patients with biochemically proven ATP synthase deficiency. Gene expression data analysis allowed classification of patients into several distinct groups, provided information on subgroup and patient specific gene expression profiles, defined candidate disease causing genes and gave basic information on pathogenic mechanisms associated with ATP synthase deficiency. Keywords: ATP synthase, mitochondrial biogenesis, ROS, gene expression, microarray, human Two-condition experiment, patients vs. controls cells. Biological replicates: 9 control, 13 patients, independently grown and harvested.
2008-08-01 | E-GEOD-10956 | biostudies-arrayexpress
Project description:Defects of mitochondrial functions lead in humans to vast array of usually multisystemic pathologies and several hundreds of diseases resulting from various defects of mitochondria biogenesis and maintenance, defects of respiratory chain complexes (OXPHOS) or defects of individual mitochondrial proteins are known. We used Agilent Whole Human Genome Microarray for gene expression profiling of genetically heterogeneous group of 13 patients with biochemically proven ATP synthase deficiency. Gene expression data analysis allowed classification of patients into several distinct groups, provided information on subgroup and patient specific gene expression profiles, defined candidate disease causing genes and gave basic information on pathogenic mechanisms associated with ATP synthase deficiency. Keywords: ATP synthase, mitochondrial biogenesis, ROS, gene expression, microarray, human
2008-08-01 | GSE10956 | GEO
Project description:Defects of mitochondrial functions lead in humans to vast array of usually multisystemic pathologies and several hundreds of diseases resulting from various defects of mitochondria biogenesis and maintenance, defects of respiratory chain complexes (OXPHOS) or defects of individual mitochondrial proteins are known. To strengthen diagnostic work-up for various mitopathies we designed focused oligonucleotide microarray which allows expression profiling of 1632 human mitochondria related genes and tested its performance in analysis of genetically heterogeneous group of 13 patients with biochemically proven ATP synthase deficiency. Gene expression data analysis allowed classification of patients into several distinct groups, provided information on subgroup and patient specific gene expression profiles, defined candidate disease causing genes and gave basic information on pathogenic mechanisms associated with ATP synthase deficiency. Keywords: ATP synthase, mitochondrial biogenesis, ROS, gene expression, microarray, human
2007-08-02 | GSE8648 | GEO
Project description:Adenosine triphosphate (ATP) synthase is located on the inner membrane of mitochondria which generate ATP for various cellular processes. Our previous studies showed that ATP synthases existed on plasma membrane of several types of cancer cells, which was defined as ectopic ATP synthase. However, the trafficking pathway of ectopic ATP synthase is still unclear. To investigate how ATP synthase subunits are involved in the trafficking process, we performed shot-gun proteomic analysis to reveal the plasma membrane proteins of A549 lung cancer cells and identified four subunits of ATP synthases, ATP5A1, ATP5B, ATP5H, and MT-ATP6. With the results of gene set enrichment analysis, we inferred that ectopic ATP synthase subunits are assembled as complex consistently and then translocated to cell surface through the trafficking of mitochondria. On the other hand, microtubules are involved in many intracellular transport. During protein trafficking, mitochondria and vesicles are transported to their final destination along microtubules by motor proteins such as kinesins and dyneins. To explore the function of microtubules in the trafficking of ectopic ATP synthase, we treated MCF-7 breast and A549 lung cancer cells with nocodazole, a microtubule depolymerization agent, and found that the expression level of ectopic ATP synthase decreased using both immunocytochemistry and flow cytometry. Besides, since kinesin family member 5B (KIF5B) is an important motor proteins involved in the transport of mitochondria, we further performed the immunoprecipitation of KIF5B followed by liquid chromatography−tandem mass spectrometry (LC−MS/MS). The result revealed that one of the mitochondrial outer membrane proteins, dynamin-1 like proteins (Drp1), was able to associate to KIF5B. From our recent research results and other reports show that Drp1 is a mediator of mitochondrial dynamic through regulation of mitochondrial fission. Taken together, our findings suggested that Drp1-KIF5B complex-mediated mitochondrial trafficking along microtubules may play a critical role in the transport of ectopic ATP synthase
2023-05-10 | PXD006791 | Pride
Project description:ATP synthase is crucial for ATP synthesis in living cells. Recently, ATP synthase was found not only in mitochondria but also on the extracellular surface, named as ectopic ATP synthase (ecto-ATP synthase). ATP synthase inhibitor is a potential drug candidate to fight cancer by blocking the ecto-ATP synthase of cells. In this study, we applied dynamic phosphoproteomics to elucidate the molecular responses to ecto-ATP synthase blockade.
2015-11-06 | PXD000701 | Pride
Project description:Ectopic ATP synthase is a functional onco-protein increases cell proliferation when transported to plasma membrane of cancer cells. Our previous study performed large scale gene silencing screening indicated ER and mitochondrial transport pathways may lead to ectopic ATP synthase expression. Silencing dynamin-related protein 1 (Drp1), mitofusin-1 (Mfn1) and Parkin affected ectopic ATP synthases expression. However, the underlying trafficking mechanism is poorly understood. Here, we analyzed our membrane and mitochondrial proteome of lung cancer A549 cells and found that both nuclear-encoded ATP synthase subunits and mitochondrial-encoded components-ATP6 translocated to cell surface, indicating that ATP synthase subunits assembled in mitochondria. Furthermore, serum starvation enhanced ATP synthase translocation to plasma membrane, Mdivi-1, a chemical inhibitor of the mitochondrial fission protein Drp1, rescued the phenomena. Additionally, image quantification of mitochondria, showing that mitochondrial fission preference cells expressed more eATP synthase. Therefore, we proposed that eATP synthase trafficking may be related to mitochondrial dynamics. Additionally, ICC and flow cytometry revealed the expression of a critical transcription factor associated with high-risk neuroblastoma, MYCN, correlated with eATP synthase expression. To better understand whether MYCN mediated mitochondrial fission and affected ATP synthase trafficking, we first analyzed MYCN ChIP-sequencing data and found Drp1, Mfns and Parkin possessed the consensus DNA-binding motif of MYCN. Further high-resolution image analysis showed higher mitochondrial fission and eATP synthase expression in MYCN-amplified neuroblastoma. Last, silencing MYCN reduced the fission level by detecting DRP1. In summary, we suggest that trafficking of ectopic ATP synthase may via mitochondrial dynamics.
2023-05-10 | PXD007036 | Pride
Project description:ATP synthase is crucial for ATP synthesis in living cells. Recently, ATP synthase was found not only in mitochondria but also on the extracellular surface, named as ectopic ATP synthase (ecto-ATP synthase). ATP synthase inhibitor is a potential drug candidate to fight cancer by blocking the ecto-ATP synthase of cancer cells. In this study, we applied dynamic phosphoproteomics to elucidate the molecular responses to ecto-ATP synthase blockade.
2015-11-06 | PXD000696 | Pride
Project description:Defects of mitochondrial functions lead in humans to vast array of usually multisystemic pathologies and several hundreds of diseases resulting from various defects of mitochondria biogenesis and maintenance, defects of respiratory chain complexes (OXPHOS) or defects of individual mitochondrial proteins are known. To strengthen diagnostic work-up for various mitopathies we designed focused oligonucleotide microarray which allows expression profiling of 1632 human mitochondria related genes and tested its performance in analysis of genetically heterogeneous group of 13 patients with biochemically proven ATP synthase deficiency. Gene expression data analysis allowed classification of patients into several distinct groups, provided information on subgroup and patient specific gene expression profiles, defined candidate disease causing genes and gave basic information on pathogenic mechanisms associated with ATP synthase deficiency. Two-condition experiment, patients vs. controls cells. Biological replicates: 9 control, 13 patients, independently grown and harvested. Two replicates per array.
2010-06-05 | E-GEOD-8648 | biostudies-arrayexpress