Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE104343 | GEO | 2018/12/31
REPOSITORIES: GEO
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Project description:Chronic obstructive pulmonary disease (COPD) is a heterogenous respiratory disease mainly caused by smoking. Respiratory infections constitute a major risk factor for acute worsening of COPD symptoms or COPD exacerbation. Mitochondrial functionality, which is crucial for the execution of physiologic functions of metabolically active cells, is impaired in airway epithelial cells (AECs) of COPD patients as well as smokers. However, the potential contribution of mitochondrial dysfunction in AECs to progression of COPD, infection-triggered exacerbations in AECs and a potential mechanistic link between mitochondrial and epithelial barrier dysfunction is unknown to date. In this study, we used an in vitro COPD exacerbation model based on AECs exposed to cigarette smoke extract (CSE) followed by infection with Streptococcus pneumoniae (Sp). The levels of oxidative stress, as an indicator of mitochondrial stress were quantified upon CSE and Sp. The expression of proteins associated with mitophagy, mitochondrial content and biogenesis as well as mitochondrial fission and fusion was quantified upon CSE and Sp. Transcriptional AEC profiling was performed to identify the potential changes in innate immune pathways and correlate them with mitochondrial function. We found that CSE exposure substantially altered mitochondrial function in AECs by suppressing mitochondrial complex protein levels, reducing mitochondrial membrane potential and increasing mitochondrial stress and mitophagy. Moreover, CSE-induced mitochondrial dysfunction correlated with reduced enrichment of genes involved in apical junctions and innate immune responses to Sp, particularly type I interferon responses. Together, our results demonstrated that CSE-induced mitochondrial dysfunction may contribute to impaired innate immune responses to Sp and may thus trigger COPD exacerbation.
2022-05-27 | GSE197751 | GEO
Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation1. Th17 cells have unique metabolic features, including a stem cell-like signature2,3 and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling4,5. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function6. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression) but dispensable in other T cell subsets. We find that Th17 cells rely on mitochondrial fusion as a result of their low metabolic activity. Thus, lowering metabolic activity in other T cell subsets by nutrient restriction was sufficient to increase reliance on mitochondrial fusion for effector function. Transcriptional, proteomic, and metabolomic profiling identified the serine/threonine kinase liver associated kinase B1 (LKB1) as an essential node coupling mitochondrial function to cytokine expression in T cells. By genetic and metabolomic approaches, we demonstrate that LKB1 regulates IL-17A expression by controlling TCA cycle metabolites and transcriptional remodeling. Th-17 cell-specific deletion of optic atrophy 1 (OPA1), a protein involved in mitochondrial inner membrane fusion and cristae organization, reduced autoimmune pathogenesis in a mouse model of multiple sclerosis, while additional deletion of LKB1 restored disease. Our findings highlight distinct mitochondrial requirements in CD4+ T cells, identify mitochondrial membrane fusion as a major determinant of Th17 responses, and reveal LKB1 as a sensor of mitochondrial integrity that links mitochondrial cues to effector programs in Th17 cells.
2022-09-19 | GSE207602 | GEO
Project description:The unique metabolic profile of most cancers (aerobic glycolysis) might confer apoptosis-resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential and low expression of the K+ channel Kv1.5, both contributing to apoptosis-resistance. Dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases mitochondrial-H2O2 and activates Kv channels in all cancer, but not normal cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation and tumor growth in vitro and in vivo, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a novel selective anticancer agent. Keywords: treatment
2006-10-11 | GSE6014 | GEO
Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation1. Th17 cells have unique metabolic features, including a stem cell-like signature2,3 and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling4,5. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function6. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression) but dispensable in other T cell subsets. We find that Th17 cells rely on mitochondrial fusion as a result of their low metabolic activity. Thus, lowering metabolic activity in other T cell subsets by nutrient restriction was sufficient to increase reliance on mitochondrial fusion for effector function. Transcriptional, proteomic, and metabolomic profiling identified the serine/threonine kinase liver associated kinase B1 (LKB1) as an essential node coupling mitochondrial function to cytokine expression in T cells. By genetic and metabolomic approaches, we demonstrate that LKB1 regulates IL-17A expression by controlling TCA cycle metabolites and transcriptional remodeling. Th-17 cell-specific deletion of optic atrophy 1 (OPA1), a protein involved in mitochondrial inner membrane fusion and cristae organization, reduced autoimmune pathogenesis in a mouse model of multiple sclerosis, while additional deletion of LKB1 restored disease. Our findings highlight distinct mitochondrial requirements in CD4+ T cells, identify mitochondrial membrane fusion as a major determinant of Th17 responses, and reveal LKB1 as a sensor of mitochondrial integrity that links mitochondrial cues to effector programs in Th17 cells.
2022-09-19 | GSE207601 | GEO
Project description:T helper 17 (Th17) cells are a distinct subset of CD4+ T cells necessary for maintaining gut homeostasis and have prominent roles in autoimmunity and inflammation1. Th17 cells have unique metabolic features, including a stem cell-like signature2,3 and reliance on mitochondrial respiratory chain function and tricarboxylic acid (TCA) cycle to coordinate metabolic and epigenetic remodeling4,5. Dynamic changes in mitochondrial membrane morphology are key to sustain organelle function6. However, it remains unclear whether mitochondrial membrane remodeling orchestrates metabolic and differentiation events in Th17 cells. Here we demonstrate that mitochondrial membrane fusion and tight cristae organization are required for Th17 cell function (i.e. cytokine expression) but dispensable in other T cell subsets. We find that Th17 cells rely on mitochondrial fusion as a result of their low metabolic activity. Thus, lowering metabolic activity in other T cell subsets by nutrient restriction was sufficient to increase reliance on mitochondrial fusion for effector function. Transcriptional, proteomic, and metabolomic profiling identified the serine/threonine kinase liver associated kinase B1 (LKB1) as an essential node coupling mitochondrial function to cytokine expression in T cells. By genetic and metabolomic approaches, we demonstrate that LKB1 regulates IL-17A expression by controlling TCA cycle metabolites and transcriptional remodeling. Th-17 cell-specific deletion of optic atrophy 1 (OPA1), a protein involved in mitochondrial inner membrane fusion and cristae organization, reduced autoimmune pathogenesis in a mouse model of multiple sclerosis, while additional deletion of LKB1 restored disease. Our findings highlight distinct mitochondrial requirements in CD4+ T cells, identify mitochondrial membrane fusion as a major determinant of Th17 responses, and reveal LKB1 as a sensor of mitochondrial integrity that links mitochondrial cues to effector programs in Th17 cells.
2022-09-19 | GSE156742 | GEO
Project description:The unique metabolic profile of most cancers (aerobic glycolysis) might confer apoptosis-resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential and low expression of the K+ channel Kv1.5, both contributing to apoptosis-resistance. Dichloroacetate (DCA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases mitochondrial-H2O2 and activates Kv channels in all cancer, but not normal cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation and tumor growth in vitro and in vivo, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a novel selective anticancer agent. Experiment Overall Design: lung carcinoma and brain glioblastoma cells were analalyzed, with microarrays run both for control and treatment with DCA
2008-06-14 | E-GEOD-6014 | biostudies-arrayexpress
Project description:This set of experiment was done in order to analyze the effect of a dysfunctional mitochondria on C. albicans. The mutant was obtained by deleting the gene FZO1, which is known to be involved in mitochondrial biogenesis in S. cerevisiae. We show that the deletion of FZO1 leads to a change in mitochondrial morphology, which affects the mitochondrial membrane potential and causes the loss of mtDNA. Upon performing a transcriptome analysis, we observed that the mutant showed upregulation of genes like AOX2, MDR1 etc., while the genes involved in iron uptake were dysregulated. Besides, genes involved in cell wall biosynthesis were also downregulated. Genotypic Technology Pvt. Ltd. designed Custom Whole Genome Candida albicans 8x15k GE Microarray (AMADID-026377).
2013-12-05 | E-GEOD-46003 | biostudies-arrayexpress
Project description:The aim is to investigate the impact of prostate and colorectal cancer on mitochondrial quantity and quality along with muscle mass and function and whether this can be modified through the use of a home-based short-term exercise training program.
The investigators aim to recruit participants awaiting curative surgery for colorectal and prostate cancer and to assess the variation in baseline mitochondrial activity between them.
Participants from both cancer types will then carry out a 4 week home exercise program, this will be randomly allocated to either resistance-based or high-intensity interval training based. Participants will then be re-assessed on the day of their planned surgical procedure to assess the changes effected by the training program.
The investigators hypothesize that there will be variation in mitochondrial activity linked to muscle mass across the two cancer types and that home-based exercise programs have the ability to improve mitochondrial activity along with muscle mass.
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Project description:The ATPase Family AAA Domain Containing 3A (ATAD3A) is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knockout (Atad3 nKO) mouse model, which developed a severe encephalopathy by 5 months of age. Pre-symptomatic mice showed aberrant mitochondrial cristae morphogenesis in the cortex as early as 2 months. Using a multi-omics approach in the CNS of 2-3-month-old mice, we found early alterations in the organelle membrane structure. We also showed that human ATAD3A associates with different components of the inner membrane, including: OXPHOS complex I, Letm1 and prohibitin complexes. Stochastic Optical Reconstruction Microscopy (STORM) showed that ATAD3A is regularly distributed along the inner mitochondrial membrane, suggesting a critical structural role in inner mitochondrial membrane and its organization, most likely in an ATPase-dependent manner.
2021-12-30 | GSE186409 | GEO
Project description:In this study, we show that within minutes of exposure to differentiation cues and activation of the electron transport chain, the mitochondrial outer membrane transiently fuses with the nuclear membrane of neural progenitors, leading to efflux of the nuclear-encoded RNAs (neRNA) into the positively charged mitochondrial intermembrane space. Subsequent degradation of mitochondrial neRNAs by Polynucleotide phosphorylase 1 (Pnpt1) residing in the intermembrane space curbs the transcriptomic memory of progenitor cells. Further, phosphorolysis by Pnpt1 indirectly suppresses ATP production by depriving ATP synthase of inorganic phosphate, resulting in delayed recovery of the attenuated transcriptomic memory. Collectively, these events force the progenitor cells towards a “tipping point” characterised by emergence of a competing neuronal differentiation program.
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