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Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.

  • Alecu I Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland.
  • Tedeschi A Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Bonn, Germany.
  • Behler N LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • Wunderling K LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • Lamberz C Cyro-Electron Microscopy and Tomography, German Center for Neurodegenerative Diseases, Bonn, Germany.
  • Lauterbach MA Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
  • Gaebler A LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • Ernst D Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland.
  • Van Veldhoven PP Laboratory for Lipid Biochemistry and Protein Interactions, Campus Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.
  • Al-Amoudi A Cyro-Electron Microscopy and Tomography, German Center for Neurodegenerative Diseases, Bonn, Germany.
  • Latz E Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
  • Othman A Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
  • Kuerschner L LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • Hornemann T Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland.
  • Bradke F Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Bonn, Germany.
  • Thiele C LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
  • Penno A LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany anke.penno@uni-bonn.de.
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  • 2016-11-25
Published in:
  • Journal of lipid research. - 2017
ES-285
chemical synthesis
diabetes
inborn errors of metabolism
lipids/chemistry
metabolic syndrome
mitotoxicity
neurons
peripheral neuropathy
sphingolipids
Animals
Diabetes Mellitus, Type 2
Diabetic Neuropathies
Hereditary Sensory and Autonomic Neuropathies
Humans
Lipids
Male
Mitochondria
Oxidoreductases
Peripheral Nerves
Sphingolipids
English 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.
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  • English
Open access status
bronze
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https://sonar.ch/global/documents/47357
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