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000138990 0247_ $$2doi$$a10.1194/jlr.M068676
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000138990 0247_ $$2ISSN$$a0022-2275
000138990 0247_ $$2ISSN$$a1539-7262
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000138990 037__ $$aDZNE-2020-05312
000138990 041__ $$aEnglish
000138990 082__ $$a540
000138990 1001_ $$aAlecu, Irina$$b0
000138990 245__ $$aLocalization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.
000138990 260__ $$aBethesda, Md.$$bASBMB$$c2017
000138990 264_1 $$2Crossref$$3online$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2016-11-23
000138990 264_1 $$2Crossref$$3print$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2017-01-01
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000138990 520__ $$a1-Deoxysphingolipids (deoxySLs) are atypical sphingolipids that are elevated in the plasma of patients with type 2 diabetes and hereditary sensory and autonomic neuropathy type 1 (HSAN1). Clinically, diabetic neuropathy and HSAN1 are very similar, suggesting the involvement of deoxySLs in the pathology of both diseases. However, very little is known about the biology of these lipids and the underlying pathomechanism. We synthesized an alkyne analog of 1-deoxysphinganine (doxSA), the metabolic precursor of all deoxySLs, to trace the metabolism and localization of deoxySLs. Our results indicate that the metabolism of these lipids is restricted to only some lipid species and that they are not converted to canonical sphingolipids or fatty acids. Furthermore, exogenously added alkyne-doxSA [(2S,3R)-2-aminooctadec-17-yn-3-ol] localized to mitochondria, causing mitochondrial fragmentation and dysfunction. The induced mitochondrial toxicity was also shown for natural doxSA, but not for sphinganine, and was rescued by inhibition of ceramide synthase activity. Our findings therefore indicate that mitochondrial enrichment of an N-acylated doxSA metabolite may contribute to the neurotoxicity seen in diabetic neuropathy and HSAN1. Hence, we provide a potential explanation for the characteristic vulnerability of peripheral nerves to elevated levels of deoxySLs.
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000138990 650_7 $$2NLM Chemicals$$aLipids
000138990 650_7 $$2NLM Chemicals$$aSphingolipids
000138990 650_7 $$0EC 1.-$$2NLM Chemicals$$aOxidoreductases
000138990 650_7 $$0EC 1.3.1.-$$2NLM Chemicals$$adihydroceramide desaturase
000138990 650_2 $$2MeSH$$aAnimals
000138990 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: blood
000138990 650_2 $$2MeSH$$aDiabetes Mellitus, Type 2: pathology
000138990 650_2 $$2MeSH$$aDiabetic Neuropathies: blood
000138990 650_2 $$2MeSH$$aDiabetic Neuropathies: pathology
000138990 650_2 $$2MeSH$$aHereditary Sensory and Autonomic Neuropathies: blood
000138990 650_2 $$2MeSH$$aHereditary Sensory and Autonomic Neuropathies: pathology
000138990 650_2 $$2MeSH$$aHumans
000138990 650_2 $$2MeSH$$aLipids: blood
000138990 650_2 $$2MeSH$$aMale
000138990 650_2 $$2MeSH$$aMitochondria: drug effects
000138990 650_2 $$2MeSH$$aMitochondria: metabolism
000138990 650_2 $$2MeSH$$aMitochondria: pathology
000138990 650_2 $$2MeSH$$aOxidoreductases: metabolism
000138990 650_2 $$2MeSH$$aPeripheral Nerves: metabolism
000138990 650_2 $$2MeSH$$aPeripheral Nerves: pathology
000138990 650_2 $$2MeSH$$aSphingolipids: blood
000138990 650_2 $$2MeSH$$aSphingolipids: chemical synthesis
000138990 650_2 $$2MeSH$$aSphingolipids: pharmacology
000138990 7001_ $$0P:(DE-2719)2810470$$aTedeschi, Andrea$$b1$$udzne
000138990 7001_ $$aBehler, Natascha$$b2
000138990 7001_ $$aWunderling, Klaus$$b3
000138990 7001_ $$0P:(DE-2719)2811203$$aLamberz, Christian$$b4$$udzne
000138990 7001_ $$aLauterbach, Mario A R$$b5
000138990 7001_ $$aGaebler, Anne$$b6
000138990 7001_ $$aErnst, Daniela$$b7
000138990 7001_ $$aVan Veldhoven, Paul P$$b8
000138990 7001_ $$0P:(DE-2719)2259138$$aAlamoudi, Ashraf$$b9$$udzne
000138990 7001_ $$0P:(DE-HGF)0$$aLatz, Eicke$$b10
000138990 7001_ $$aOthman, Alaa$$b11
000138990 7001_ $$aKuerschner, Lars$$b12
000138990 7001_ $$aHornemann, Thorsten$$b13
000138990 7001_ $$0P:(DE-2719)2810270$$aBradke, Frank$$b14$$udzne
000138990 7001_ $$aThiele, Christoph$$b15
000138990 7001_ $$0P:(DE-HGF)0$$aPenno, Anke$$b16$$eCorresponding author
000138990 77318 $$2Crossref$$3journal-article$$a10.1194/jlr.m068676$$b : American Society for Biochemistry & Molecular Biology (ASBMB), 2016-11-23$$n1$$p42-59$$tJournal of Lipid Research$$v58$$x0022-2275$$y2016
000138990 773__ $$0PERI:(DE-600)1466675-3$$a10.1194/jlr.M068676$$gVol. 58, no. 1, p. 42 - 59$$n1$$p42-59$$q58:1<42 - 59$$tJournal of lipid research$$v58$$x0022-2275$$y2017
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000138990 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234710
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