Regulation of mitochondrial ceramide distribution by members of the BCL-2 family

Zhang, Tejia; Barclay, Lauren A.; Walensky, Loren D.; Saghatelian, Alan

doi:10.1194/jlr.m058750

Cited by 22 publications

(20 citation statements)

References 60 publications

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“…Free SAdienes and synthetic analogues exhibit cytotoxic and anti-proliferative effects in cancer and noncancer cells (30,31) and were associated with the inhibition of colon tumorigenesis in mouse models (32,33). Mitochondrial and cellular pools of d18:2-based ceramides were elevated in embryonic fibroblasts derived from double-knockout BAX-BAK mice and a mousederived immortalized iBMK cell line (34). It is noteworthy that the ⌬14 DB in d18:2 is in cis conformation, introducing a kink into the otherwise straight LCB structure.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…1-deoxySO bears a (14Z) instead of a (4E) DB indicates that the metabolism of 1-deoxySL deviates from that of canonical sphingolipids. Interestingly, sphingadiene, a polyunsaturated downstream product of sphingosine (17), has double bonds at both the (4E) and (14Z) positions (Fig. 5C).…”

Section: Retention-time Correlation Of Native Lipids With Synthetic Smentioning

confidence: 99%

Elucidating the chemical structure of native 1-deoxysphingosine

Steiner

Saied

Othman

et al. 2016

Journal of Lipid Research

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Sphingolipids are typically formed by the condensation of serine and palmitoyl-CoA, a reaction catalyzed by the serine-palmitoyltransferase (SPT) enzyme. Besides these canonical substrates, SPT can use other acyl-CoAs, but also alanine or glycine, as substrates, which then form a category of atypical 1-deoxysphingolipids (1-deoxySLs) that lack the C1-OH group of canonical sphingolipids (1, 2).Several missense mutations in SPT, which are associated with the rare inherited neuropathy, HSAN1, induce a permanent shift in the substrate specificity of the enzyme resulting in increased 1-deoxySL formation. HSAN1 is a rare autosomal and dominantly inherited axonopathy and is clinically characterized by a progressive loss of pain and Abstract The 1-deoxysphingolipids (1-deoxySLs) are formed by an alternate substrate usage of the enzyme, serine-palmitoyltransferase, and are devoid of the C1-OHgroup present in canonical sphingolipids. Pathologically elevated 1-deoxySL levels are associated with the rare inherited neuropathy, HSAN1, and diabetes type 2 and might contribute to  cell failure and the diabetic sensory neuropathy. In analogy to canonical sphingolipids, it was assumed that 1-deoxySLs also bear a (4E) double bond, which is normally introduced by sphingolipid delta(4)-desaturase 1. This, however, was never confirmed. We therefore supplemented HEK293 cells with isotope-labeled D 3 -1-deoxysphinganine and compared the downstream formed D 3 -1-deoxysphingosine (1-deoxySO) to a commercial synthetic SPH m18:1(4E)(3OH) standard. Both compounds showed the same m/z, but differed in their RPLC retention time and atmospheric pressure chemical ionization in-source fragmentation, suggesting that the two compounds are structural isomers. Using dimethyl disulfide derivatization followed by MS 2 as well as differential-mobility spectrometry combined with ozone-induced dissociation MS, we identified the carbon-carbon double bond in native 1-deoxySO to be located at the (14) position. Comparing the chromatographic behavior of native 1-deoxySO to chemically synthesized SPH m18:1(14Z) and (14E) stereoisomers assigned the native compound to be SPH m18:1(14Z). This indicates that 1-deoxySLs are metabolized differently than canonical

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“…Sphingosine kinases remain targets of interest for cancer therapy, and inhibitors of both SphK1 and SphK2 have been investigated in clinical trials. Our findings demonstrate the importance of analyzing and better understanding the functional significance of sphingadiene lipids, particularly given that circulating levels of these lipids were reported as significantly higher in females (49), and knockout of SphK2, or Bax and Bak (58), has now been shown to alter the balance between sphingadiene-and sphingosine-containing lipids. which can be recycled back to ceramide in the salvage pathway or phosphorylated by SphK1 or SphK2, forming S1P.…”

Section: Discussionmentioning

confidence: 68%

A novel function of sphingosine kinase 2 in the metabolism of sphinga-4,14-diene lipids

Couttas

Rustam

Song

et al. 2020

Preprint

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Abbreviations: CID: collision induced dissociation; HexCer: hexosylceramide; LC-MS/MS: liquid chromatography-tandem mass spectrometry; SM: sphingomyelin; SphK1: sphingosine kinase 1; SphK2: sphingosine kinase 2; UVPD: ultraviolet photodissociation. AbstractThe number, position, and configuration of double bonds in lipid acyl chains affects membrane packing, fluidity, and recruitment of signalling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Sphingolipids with a diunsaturated sphingadiene base have been reported but are poorly characterised. Employing high-resolution untargeted mass spectrometry, we observed marked accumulation of lipids containing a sphingadiene base, but not those with a more common sphingosine backbone, in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). Applying ultraviolet photodissociation tandem mass spectrometry (UVPD-MS/MS) the double bonds were confidently assigned to the C4-C5 and C14-C15 positions of the sphingoid base. Sphingosine kinases are involved in lysosomal catabolism of all sphingolipids, producing sphingoid base phosphates that are irreversibly degraded by sphingosine 1-phosphate lyase. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments demonstrated that ceramides with a sphingosine base are more rapidly metabolised in cultured cells than those with a sphingadiene base. SphK2 silencing significantly impeded the catabolism of both sphingosine-and sphingadiene-based sphingolipids. Since SphK2 is the dominant sphingosine kinase in brain, we propose that accumulation of sphingadiene lipids in SphK2-deficient brains results from the intrinsically slower catabolism of sphingadiene lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We speculate that accumulation of these lipids in the absence of SphK2 function may affect the fluidity and signalling properties of cell membranes.

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Regulation of mitochondrial ceramide distribution by members of the BCL-2 family

Cited by 22 publications

References 60 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

Elucidating the chemical structure of native 1-deoxysphingosine

A novel function of sphingosine kinase 2 in the metabolism of sphinga-4,14-diene lipids

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