Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling
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ABSTRACT:
PROVIDER: PRJNA674653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12982935_1.fastq.gz | Fastqsanger.gz | |||
| SRR12982935_2.fastq.gz | Fastqsanger.gz | |||
| SRR12982936_1.fastq.gz | Fastqsanger.gz | |||
| SRR12982936_2.fastq.gz | Fastqsanger.gz | |||
| SRR12982937_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle phosphatidic acid (PA) synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the cardiolipin synthase Crd1, Ups1 deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1D cells leads to altered phospholipid composition of the ER membrane, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine (PC) and a reduced phosphatidylethanolamine (PE)/PC ratio in the ER of ups1D cells which suppresses the unfolded protein response (UPR). Moreover, we observed inhibition of TORC1 signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the SEACIT complex, increased cytosolic protein synthesis and restored glycolytic growth of ups1D cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.
2021-01-21 | GSE160861 | GEO
Project description:Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle phosphatidic acid (PA) synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the cardiolipin synthase Crd1, Ups1 deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1 cells leads to altered phospholipid composition of the ER membrane, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine (PC) and a reduced phosphatidylethanolamine (PE)/PC ratio in the ER of ups1 cells which suppresses the unfolded protein response (UPR). Moreover, we observed inhibition of TORC1 signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the SEACIT complex, increased cytosolic protein synthesis and restored glycolytic growth of ups1 cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.
2021-01-22 | PXD022321 | Pride
Project description:Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle phosphatidic acid (PA) mainly synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the CL synthase Crd1, Ups1-deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1Δ cells leads to altered unfolded protein response (UPR) and mTORC1 signaling, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine and a reduced phosphatidylethanolamine/phosphatidylcholine ratio in the ER of ups1Δ cells which suppresses the UPR. Moreover, we observed inhibition of target of rapamycin complex 1 (TORC1) signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the Seh1-associated complex inhibiting TORC1 complex, increased cytosolic protein synthesis, and restored glycolytic growth of ups1Δ cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.
| S-EPMC7949116 | biostudies-literature
Project description:au10-12_pa - phosphatidic acid in gene expression - Role of DGK in gene expression - Compounds were added 4h before cell harvesting.
2012-03-01 | GSE35872 | GEO
Project description:au10-12_pa - phosphatidic acid in gene expression - Role of DGK in gene expression - Compounds were added 4h before cell harvesting. 6 dye-swap - treated vs untreated comparison
2012-03-01 | E-GEOD-35872 | biostudies-arrayexpress
Project description:Our goal is to identify Salycilic Acid responsive genes dependent on PLD activation. - The experiment is done on Arabidopsis suspension cells, ecotype Columbia : Research of phospholipase D (PLD) activity implication in the response to SA. The use of primary alcohol, like N-butanol, makes possible to derive PLD activity towards the production of phosphatidylalcohol with the detriment of phosphatidic acid, the product of the PLD. Thus, in the presence of n-butanol, the response of the genes to SA dependent on phosphatidic acid will see their response disturbed. On the contrary, in the presence of tertiary butanol, the response of the genes should not be disturbed, tertiary alcohols not acting on the PLD. Keywords: treated vs untreated comparison
2007-11-29 | GSE9695 | GEO
Project description:Using a systematic proteomic approach, we define the protein-protein interaction network for PLD superfamily and phosphatidic acid in human cells and reveal diverse cellular signaling events involved for this key protein family and lipid.
2022-01-16 | PXD029183 | Pride
Project description:Genome-wide association studies and physiological investigations have linked alterations in acid-base transporters to hypertension. Accordingly, Na(+)-coupled HCO(-) 3-transporters, Na(+)/H(+)-exchangers, and anion-exchangers have emerged as putative mechanistic components in blood pressure disturbances. Even though hypertension has been studied extensively over the last several decades, the cause of the high blood pressure has in most cases not been identified. Renal, cardiovascular, and neuronal dysfunctions all seem to play a role in hypertension development but their relative importance and mutual interdependency are still being debated. Multiple functional and structural alterations have been described in patients and animals with hypertension but it is typically unclear whether they are causes or consequences of hypertension or represent mechanistically unrelated associations. Perturbed blood pressure regulation has been demonstrated in several animal models with disrupted expression of acid-base transporters; and reciprocally, disturbed acid-base transport function has been described in hypertensive individuals. In addition to regulating intracellular and extracellular pH, Na(+)-coupled HCO(-) 3-transport, Na(+)/H(+)-exchange, and anion-exchange also contribute to water and electrolyte balance in cells and systemically. Since acid-base transporters are widely expressed, alterations in transport activities likely affect multiple cell and organ functions, and it is a significant challenge to determine the mechanisms linking perturbed acid-base transport function to hypertension. It is the purpose of this review to evaluate the current evidence for involvement of acid-base transporters in hypertension development and discuss the cellular and integrative mechanisms, which may link changes in acid-base transport to blood pressure disturbances.
| S-EPMC3870919 | biostudies-literature
Project description:Ups1 forms a complex with Mdm35 and is critical for the transport of phosphatidic acid (PA) from the mitochondrial outer membrane to the inner membrane. We report the crystal structure of the Ups1-Mdm35-PA complex and the functional characterization of Ups1-Mdm35 in PA binding and transfer. Ups1 features a barrel-like structure consisting of an antiparallel β-sheet and three α-helices. Mdm35 adopts a three-helical clamp-like structure to wrap around Ups1 to form a stable complex. The β-sheet and α-helices of Ups1 form a long tunnel-like pocket to accommodate the substrate PA, and a short helix α2 acts as a lid to cover the pocket. The hydrophobic residues lining the pocket and helix α2 are critical for PA binding and transfer. In addition, a hydrophilic patch on the surface of Ups1 near the PA phosphate-binding site also plays an important role in the function of Ups1-Mdm35. Our study reveals the molecular basis of the function of Ups1-Mdm35 and sheds new light on the mechanism of intramitochondrial phospholipid transport by the MSF1/PRELI family proteins.
| S-EPMC4515121 | biostudies-literature
Project description:Cells tightly control the homeostatic levels and subcellular localizations of membrane phospholipids through the regulation of the activities of numerous lipid-metabolizing enzymes and lipid transfer proteins. Yet, the mechanisms by which lipid imbalances are sensed and corrected to establish and maintain homeostasis are, in many cases, unknown. Here we present an expanded view of plasma membrane phosphoinositide metabolism by revealing an unexpected metabolic connection between two key anionic lipids in this membrane, phosphatidylinositol 4-phosphate (PI4P) and phosphatidic acid (PA). Plasma membrane pools of PI4P are generated by PI 4-kinase Type IIIα (PI4KIIIα/PI4KA), an essential enzyme whose partial dysfunction leads to numerous hereditary human diseases. We find that depletion of PI4P by pharmacological inhibition of PI4KA increases the activity of phospholipase Ds (PLDs) and the levels of their lipid product, PA. Guided by RNA-seq analysis and proximity labeling proteomics, we elucidate how cells connect this PI4P decrease to a compensatory increase in PA levels. Loss of plasma membrane PI4P induces a concomitant decrease of phosphatidylserine (PS) levels, and this metabolic rewiring activates a reciprocal relationship between PS synthesis and PLD-mediated PA generation. These metabolic changes lead to transcriptional and translational upregulation of the small GTPase RhoB, which enhances PLD-mediated PA synthesis and subsequent actin cytoskeletal remodeling. Our study reveals how disease-relevant perturbation of phosphoinositide synthesis induces an integrated response that ultimately boosts levels of a key anionic lipid and metabolic intermediate in phosphoinositide resynthesis.
2025-12-04 | GSE308521 | GEO