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Alternate assembly of SDHA connects energy stress to metabolic checkpoint and DNA synthesis

ABSTRACT: Alternate assembly of SDHA connects energy stress to metabolic checkpoint and DNA synthesis

OTHER RELATED OMICS DATASETS IN: PXD009656

PROVIDER: PRJNA429204 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6451710.fastq.gz	Fastqsanger.gz
	SRR6451711.fastq.gz	Fastqsanger.gz
	SRR6451704.fastq.gz	Fastqsanger.gz
	SRR6451705.fastq.gz	Fastqsanger.gz
	SRR6451706.fastq.gz	Fastqsanger.gz

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Alternate assembly of SDHA connects energy stress to metabolic checkpoint and DNA synthesis

Project description:Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. We have discovered that an alternative mitochondrial complex II (CII) assembly, designated here as CIIlow, serves as a check-point for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CIIlow leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings uncover a new core complex inside mitochondria that provides homeostatic control of cellular metabolism to reflect availability of energy, with SDHA being its central molecule.

2018-04-16 | GSE108938 | GEO

Respiratory complex II - Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints

Project description:Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints

2018-10-18 | PXD009656 | Pride

Rad53 checkpoint kinase couples leading and lagging strand DNA synthesis

Project description:In response to DNA replication stress, DNA replication checkpoint is activated to maintain fork stability, a process critical for maintenance of genome stability. However, how DNA replication checkpoint regulates replication forks remain elusive. Here we show that Rad53, a highly conserved replication checkpoint kinase, functions to couple leading and lagging strand DNA synthesis. In wild type cells under HU induced replication stress, synthesis of lagging strand, which contains ssDNA gaps, is comparable to leading strand DNA. In contrast, synthesis of lagging strand is much more than leading strand, and consequently, leading template ssDNA coated with ssDNA binding protein RPA was detected in rad53-1 mutant cells, suggesting that synthesis of leading strand and lagging strand DNA is uncoupled. Mechanistically, we show that replicative helicase MCM and leading strand DNA polymerase Pole move beyond actual DNA synthesis and that an increase in dNTP pools largely suppresses the uncoupled leading and lagging strand DNA synthesis. Our studies reveal an unexpected mechanism whereby Rad53 regulates replication fork stability.

2018-02-11 | GSE89721 | GEO

Variability in energy metabolism enzymes in tumor cells.

Project description:Variability in gene expression is an important and largely unknown phenomenon responsible of tumor resistance to chemotherapy. Here, we show that energy metabolism proteins are highly variable, specially Glut1, G6PD, PKM2 and SDHA. In contrast, the variability of housekeeping proteins was low. We identified the PI3K/Akt/mTor pathway as the source of variability for PKM2.Variability was independent of the energy source used. However, cells grown on glucose down-regulate G6PDH and SDHA, promoting oxidative stress. Variability and chemotherapy plasticity were directly related, and the combination of drugs with opposite effect on the expression of plastic proteins resulted in positive synergy. Human solid tumor cells displayed higher variability in metabolic enzymes than cultured cells. The most aggressive tumors showed higher variability than less aggressive ones. This suggests that variability in energy metabolism enzymes could be a biomarker for tumor stratification and therapy election.

2022-03-05 | GSE127900 | GEO

Cardiolipin Synthesis Governs Systemic Energy Homeostasis through Thermogenic Fat Mitochondria

Project description:Cardiolipin Synthesis Governs Systemic Energy Homeostasis through Thermogenic Fat Mitochondria

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Cardiolipin Synthesis Governs Systemic Energy Homeostasis through Thermogenic Fat Mitochondria

Project description:Here we show that synthesis of the mitochondrial phospholipid cardiolipin is an indispensable driver of thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response by overexpressing cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency diminishes mitochondrial uncoupling in brown and beige adipocytes and elicits a nuclear transcriptional response through ER stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake and renders animals strikingly insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin is a powerful regulator of organismal energy homeostasis through thermogenic fat bioenergetics.

2018-07-19 | GSE110297 | GEO

Aflatoxin B1 attenuates endocrine function, protein synthesis and energy production of human primary trophoblast

Project description:Aflatoxin B1 attenuates endocrine function, protein synthesis and energy production of human primary trophoblast

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Alternative assembly of respiratory complex II connects energy stress to metabolic checkpoints.

Project description:Cell growth and survival depend on a delicate balance between energy production and synthesis of metabolites. Here, we provide evidence that an alternative mitochondrial complex II (CII) assembly, designated as CIIlow, serves as a checkpoint for metabolite biosynthesis under bioenergetic stress, with cells suppressing their energy utilization by modulating DNA synthesis and cell cycle progression. Depletion of CIIlow leads to an imbalance in energy utilization and metabolite synthesis, as evidenced by recovery of the de novo pyrimidine pathway and unlocking cell cycle arrest from the S-phase. In vitro experiments are further corroborated by analysis of paraganglioma tissues from patients with sporadic, SDHA and SDHB mutations. These findings suggest that CIIlow is a core complex inside mitochondria that provides homeostatic control of cellular metabolism depending on the availability of energy.

| S-EPMC5992162 | biostudies-literature

DNA replication and DSB factor binding in the meiotic S-phase checkpoint in budding yeast

Project description:During gamete formation, crossover recombination must occur on replicated DNA to ensure proper chromosome segregation in the first meiotic division. We identified a Mec1/ATR-dependent replication checkpoint in budding yeast that prevented the earliest stage of recombination, the programmed induction of DNA double-strand breaks (DSBs), when pre-meiotic DNA replication was delayed. The checkpoint suppressed DSBs through three complementary mechanisms: inhibition of Mer2 phosphorylation by Dbf4-dependent Cdc7 kinase, preclusion of chromosomal loading of Rec114 and Mre11, and lowered abundance of the Spo11 nuclease. Without this checkpoint, cells formed DSBs on partially replicated chromosomes. Importantly, such DSBs frequently failed to be repaired and impeded further DNA synthesis, leading to a rapid loss in cell viability. We conclude that a checkpoint-dependent constraint of DSB formation to duplicated DNA is critical not only for meiotic chromosome assortment, but also to protect genome integrity during gametogenesis. DSB factor association was measured in wild-type and checkpoint mutants strains under non-inducing or replication checkpoint inducing conditions. Additionally, DNA replication and helicase loading were measured in a replication and checkpoint deficient strain (cdc6-mn).

2013-09-20 | E-GEOD-46841 | biostudies-arrayexpress

Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer

Project description:Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signaling, and energy production, how specific lipids contribute to tumorigenesis is incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumor growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer (NK) and CD8+ T cells partly via interferon gamma (IFNg) signaling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNg receptor subunit 1 (Ifngr1), mediating IFNg-induced growth arrest and proinflammatory signaling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumor immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.

2024-06-30 | GSE270660 | GEO

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