title: Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.
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.
authors.affiliation: Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland.|Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Irina
authors.initials: I
authors.lastname: Alecu
authors.affiliation: Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tedeschi
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Natascha
authors.initials: N
authors.lastname: Behler
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Wunderling
authors.affiliation: Cyro-Electron Microscopy and Tomography, German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lamberz
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
authors.forename: Mario A R
authors.initials: MA
authors.lastname: Lauterbach
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gaebler
authors.affiliation: Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ernst
authors.affiliation: Laboratory for Lipid Biochemistry and Protein Interactions, Campus Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.affiliation: Cyro-Electron Microscopy and Tomography, German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Al-Amoudi
authors.affiliation: Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
authors.forename: Alaa
authors.initials: A
authors.lastname: Othman
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kuerschner
authors.affiliation: Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland.|Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.affiliation: Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Bonn, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bradke
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiele
authors.affiliation: LIMES Life and Medical Sciences Institute, University of Bonn, Bonn, Germany anke.penno@uni-bonn.de.
authors.forename: Anke
authors.initials: A
authors.lastname: Penno
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000097:blood* / Q000473:pathology; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000097:blood* / Q000473:pathology; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D013107:Sphingolipids / Q000097:blood* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D008055:Lipids; D013107:Sphingolipids; D010088:Oxidoreductases; C108138:dihydroceramide desaturase
keywords: ES-285; chemical synthesis; diabetes; inborn errors of metabolism; lipids/chemistry; metabolic syndrome; mitotoxicity; neurons; peripheral neuropathy; sphingolipids