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@ARTICLE{Alecu:138990,
      author       = {Alecu, Irina and Tedeschi, Andrea and Behler, Natascha and
                      Wunderling, Klaus and Lamberz, Christian and Lauterbach,
                      Mario A R and Gaebler, Anne and Ernst, Daniela and Van
                      Veldhoven, Paul P and Alamoudi, Ashraf and Latz, Eicke and
                      Othman, Alaa and Kuerschner, Lars and Hornemann, Thorsten
                      and Bradke, Frank and Thiele, Christoph and Penno, Anke},
      title        = {{L}ocalization of 1-deoxysphingolipids to mitochondria
                      induces mitochondrial dysfunction.},
      journal      = {Journal of lipid research},
      volume       = {58},
      number       = {1},
      issn         = {0022-2275},
      address      = {Bethesda, Md.},
      publisher    = {ASBMB},
      reportid     = {DZNE-2020-05312},
      pages        = {42-59},
      year         = {2017},
      abstract     = {1-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.},
      keywords     = {Animals / Diabetes Mellitus, Type 2: blood / Diabetes
                      Mellitus, Type 2: pathology / Diabetic Neuropathies: blood /
                      Diabetic Neuropathies: pathology / Hereditary Sensory and
                      Autonomic Neuropathies: blood / Hereditary Sensory and
                      Autonomic Neuropathies: pathology / Humans / Lipids: blood /
                      Male / Mitochondria: drug effects / Mitochondria: metabolism
                      / Mitochondria: pathology / Oxidoreductases: metabolism /
                      Peripheral Nerves: metabolism / Peripheral Nerves: pathology
                      / Sphingolipids: blood / Sphingolipids: chemical synthesis /
                      Sphingolipids: pharmacology / Lipids (NLM Chemicals) /
                      Sphingolipids (NLM Chemicals) / Oxidoreductases (NLM
                      Chemicals) / dihydroceramide desaturase (NLM Chemicals)},
      cin          = {AG Bradke / AG Alamoudi},
      ddc          = {540},
      cid          = {I:(DE-2719)1013002 / I:(DE-2719)1013012},
      pnm          = {341 - Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27881717},
      pmc          = {pmc:PMC5234710},
      doi          = {10.1194/jlr.M068676},
      url          = {https://pub.dzne.de/record/138990},
}