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Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Saccharomyces cerevisiae S288C

PROVIDER: GSE140354 | GEO | 2019/11/14

REPOSITORIES: GEO

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Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants.

Project description:The electron transport chain (ETC) is a well-studied and highly conserved metabolic pathway that produces ATP through generation of a proton gradient across the inner mitochondrial membrane coupled to oxidative phosphorylation. ETC mutations are associated with a wide array of human disease conditions and to aging-related phenotypes in a number of different organisms. In this study, we sought to better understand the role of the ETC in aging using a yeast model. A panel of ETC mutant strains that fail to survive starvation was used to isolate suppressor mutants that survive. These suppressors tend to fall into major nutrient sensing and signaling pathways, suggesting that the ETC is involved in proper starvation signaling to these pathways in yeast. These suppressors also partially restore ETC-associated gene expression and pH homeostasis defects, though it remains unclear whether these phenotypes directly cause the suppression or are simply effects. This work further highlights the complex cellular network connections between metabolic pathways and signaling events in the cell and their potential roles in aging and age-related diseases.

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Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants (ETC_Mutants)

Project description:Here we sought to comprehensively characterize the role of the electron transport chain in yeast models of aging. Using a panel of ETC mutants, we observed that ETC mutants fail to survive starvation when grown to saturation in standard SD growth medium. This starvation lethality is associated with a significantly lower cytosolic pH and dysregulated gene expression compared to wild type cells. In an unbiased genetic suppressor screen, we found that loss of function mutations in major cellular nutrient sensing/signaling pathways (Ras/PKA, Tor, PP2A) along with a number of gene expression regulators can prevent starvation lethality in these mutants. Together our results suggest that the ETC plays a critical regulatory role in mounting an appropriate response to starvation through communication with major nutrient sensing/signaling pathways in the cell.

2019-11-14 | GSE140352 | GEO

Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants (DenseTimeCourse)

2019-11-14 | GSE140353 | GEO

Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants

Project description:Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants

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Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants (ETC_Mutants)

Project description:Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants (ETC_Mutants)

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Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants (DenseTimeCourse)

Project description:Loss of major nutrient sensing and signaling pathways suppresses starvation lethality in electron transport chain mutants (DenseTimeCourse)

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Electron Transport Chain Remodeling by GSK3 during Oogenesis Connects Nutrient State to Reproduction.

Project description:Reproduction is heavily influenced by nutrition and metabolic state. Many common reproductive disorders in humans are associated with diabetes and metabolic syndrome. We characterized the metabolic mechanisms that support oogenesis and found that mitochondria in mature Drosophila oocytes enter a low-activity state of respiratory quiescence by remodeling the electron transport chain (ETC). This shift in mitochondrial function leads to extensive glycogen accumulation late in oogenesis and is required for the developmental competence of the oocyte. Decreased insulin signaling initiates ETC remodeling and mitochondrial respiratory quiescence through glycogen synthase kinase 3 (GSK3). Intriguingly, we observed similar ETC remodeling and glycogen uptake in maturing Xenopus oocytes, suggesting that these processes are evolutionarily conserved aspects of oocyte development. Our studies reveal an important link between metabolism and oocyte maturation.

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Rewiring the Mitochondrial Electron Transport Chain Enhances Tumor Immunogenicity

Project description:Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of Complex I (CI) and II (CII), the gatekeepers for initiating electron flow, remains unclear. Here, we report that loss of CII, but not CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex I-antigen processing and presentation (MHC-APP) genes that is independent of interferon signaling. Furthermore, knock-out of MCJ, to promote electron entry preferentially via CI, provides proof-of-concept of ETC rewiring to achieve anti-tumor responses without side effects associated with an overall reduction in mitochondrial respiration in non-cancer cells. Our results hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

2024-05-01 | GSE235311 | GEO

ROS-based lethality of <i>Caenorhabditis elegans</i> mitochondrial electron transport mutants grown on <i>Escherichia coli</i> siderophore iron release mutants.

Project description:Caenorhabditis elegans consumes bacteria, which can supply essential vitamins and cofactors, especially for mitochondrial functions that have a bacterial ancestry. Therefore, we screened the Keio Escherichia coli knockout library for mutations that induce the C. elegans hsp-6 mitochondrial damage response gene, and identified 45 E. coli mutations that induce hsp-6::gfp We tested whether any of these E. coli mutations that stress the C. elegans mitochondrion genetically interact with C. elegans mutations in mitochondrial functions. Surprisingly, 4 E. coli mutations that disrupt the import or removal of iron from the bacterial siderophore enterobactin were lethal in combination with a collection of C. elegans mutations that disrupt particular iron-sulfur proteins of the electron transport chain. Bacterial mutations that fail to synthesize enterobactin are not synthetic lethal with these C. elegans mitochondrial mutants; it is the enterobactin-iron complex that is lethal in combination with the C. elegans mitochondrial mutations. Antioxidants suppress this inviability, suggesting that reactive oxygen species (ROS) are produced by the mutant mitochondria in combination with the bacterial enterobactin-iron complex.

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Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

Project description:The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of NLRP3 inflammasome through multiple mechanisms including generation of mitochondrial ROS. Here we report that mitochondrial electron transport chain (ETC) complexes I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase (AOX), which can respectively complement the functional loss of mitochondrial complex I or III, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP but a ROS independent mechanism.

2022-03-09 | GSE197606 | GEO

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