1-Deoxydihydroceramide causes anoxic death by impairing chaperonin-mediated protein folding

Hannich, J. Thomas; Haribowo, A. Galih; Gentina, Sébastien; Paillard, Mélanie; Gomez, Ludovic; Pillot, Bruno; Thibault, Hélène; Abegg, Daniel; Guex, Nicolas; Adibekian, Alexander; Ovize, Michel; Martinou, Jean‐Claude; Riezman, Howard

doi:10.1038/s42255-019-0123-y

Cited by 17 publications

(36 citation statements)

References 46 publications

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“…3E). This supports recent reports indicating that m18:0 based 1-deoxySL species are more associated with toxic effects than their unsaturated forms (39). In that respect, FADS3 might contribute to a physiological detoxification of 1-deoxySLs.…”

Section: Discussionsupporting

confidence: 91%

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

Karsai

Lone

Kutalik

et al. 2020

Journal of Biological Chemistry

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Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Δ4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Δ14Z position. The enzyme introducing the Δ14Z DB is unknown. We analyzed the LCB plasma profile in a gender-, age-, and BMI-matched subgroup of the CoLaus cohort (n = 658). Sphingadienine levels showed a significant association with gender, being on average ∼30% higher in females. A genome-wide association study (GWAS) revealed variants in the fatty acid desaturase 3 (FADS3) gene to be significantly associated with the plasma d18:2/d18:1 ratio (p = −log 7.9). Metabolic labeling assays, FADS3 overexpression and knockdown approaches, and plasma LCB profiling in FADS3-deficient mice confirmed that FADS3 is a bona fide LCB desaturase and required for the introduction of the Δ14Z double bond. Moreover, we showed that FADS3 is required for the conversion of the atypical cytotoxic 1-deoxysphinganine (1-deoxySA, m18:0) to 1-deoxysphingosine (1-deoxySO, m18:1). HEK293 cells overexpressing FADS3 were more resistant to m18:0 toxicity than WT cells. In summary, using a combination of metabolic profiling and GWAS, we identified FADS3 to be essential for forming Δ14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a Δ14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL de novo synthesis pathway.

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Section: Discussionsupporting

confidence: 91%

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

Karsai

Lone

Kutalik

et al. 2020

Journal of Biological Chemistry

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“…Notably, the localization of our WALP reporters was strongly affected by ceramide length. Cells living on short ceramide (C18:16), due to the replacement of the endogenous ceramide synthases (Lac1 and Lag1) by CerS5 ( 31 ), showed enrichment of WALP23 and all longer WALPs into RITs similar to those observed with WALP27-WALP29 in wild-type cells ( Fig. 4, A and C ).…”

Section: Resultssupporting

confidence: 65%

“…These experiments established that ceramide length in these cells was determined by the enzyme expressed (30,31). Furthermore, under standard conditions, these cells grew as well as wild-type cells (31,32), unlike yeast cells lacking ceramide synthase, which are not viable. Thus, under normal conditions, yeast cells grow virtually as well with short as with long ceramides (30).…”

Section: Ceramide Drives Rits' Formationmentioning

confidence: 77%

“…Previous work established that yeast ceramide synthases can be replaced by the mammalian enzymes (30)(31)(32). These experiments established that ceramide length in these cells was determined by the enzyme expressed (30,31). Furthermore, under standard conditions, these cells grew as well as wild-type cells (31,32), unlike yeast cells lacking ceramide synthase, which are not viable.…”

Section: Ceramide Drives Rits' Formationmentioning

confidence: 94%

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Mapping bilayer thickness in the ER membrane

2020

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In the plasma membrane and in synthetic membranes, resident lipids may laterally unmix to form domains of distinct biophysical properties. Whether lipids also drive the lateral organization of intracellular membranes is largely unknown. Here, we describe genetically encoded fluorescent reporters visualizing local variations in bilayer thickness. Using them, we demonstrate that long-chained ceramides promote the formation of discrete domains of increased bilayer thickness in the yeast ER, particularly in the future plane of cleavage and at ER–trans-Golgi contact sites. Thickening of the ER membrane in the cleavage plane contributed to the formation of lateral diffusion barriers, which restricted the passage of short, but not long, protein transmembrane domains between the mother and bud ER compartments. Together, our data establish that the ER membrane is laterally organized and that ceramides drive this process, and provide insights into the physical nature and biophysical mechanisms of the lateral diffusion barriers that compartmentalize the ER.

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“…Mice were randomized to receive 25 µl of an adenovirus solution (CypD mutants at 5 × 10 8 PFU), which was injected in 10-12 different sites of the LV wall to cover the maximum area of the area at risk 58 . The chest cavity was closed, and the mice were allowed to recover for 1 week prior to I/R surgery.…”

Section: In Vivo Model Of Ischemia/reperfusion (I/r)mentioning

confidence: 99%

Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion

et al. 2020

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The mitochondrial permeability transition pore (mPTP) plays a critical role in the pathogenesis of cardiovascular diseases, including ischemia/reperfusion injury. Although the pore structure is still unresolved, the mechanism through which cyclophilin D (CypD) regulates mPTP opening is the subject of intensive studies. While post-translational modifications of CypD have been shown to modulate pore opening, specific phosphorylation sites of CypD have not yet been identified. We hypothesized here that phosphorylation of CypD on a serine residue controls mPTP opening and subsequent cell death at reperfusion. We combined in silico analysis with in vitro and genetic manipulations to determine potential CypD phosphorylation sites and their effect on mitochondrial function and cell death. Importantly, we developed an in vivo intramyocardial adenoviral strategy to assess the effect of the CypD phosphorylation event on infarct size. Our results show that although CypD can potentially be phosphorylated at multiple serine residues, only the phosphorylation status at S191 directly impacts the ability of CypD to regulate the mPTP. Protein-protein interaction strategies showed that the interaction between CypD and oligomycin sensitivityconferring protein (OSCP) was reduced by 45% in the phosphoresistant S191A mutant, whereas it was increased by 48% in the phosphomimetic S191E mutant cells. As a result, the phosphoresistant CypD S191A mutant was protected against 18 h starvation whereas cell death was significantly increased in phosphomimetic S191E group, associated with mitochondrial respiration alteration and ROS production. As in vivo proof of concept, in S191A phosphoresistant rescued CypD-KO mice developed significantly smaller infarct as compared to WT whereas infarct size was drastically increased in S191E phosphomimetic rescued mice. We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.

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1-Deoxydihydroceramide causes anoxic death by impairing chaperonin-mediated protein folding

Cited by 17 publications

References 46 publications

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome

Mapping bilayer thickness in the ER membrane

Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion

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