TY  - JOUR
AU  - Alecu, Irina
AU  - Tedeschi, Andrea
AU  - Behler, Natascha
AU  - Wunderling, Klaus
AU  - Lamberz, Christian
AU  - Lauterbach, Mario A R
AU  - Gaebler, Anne
AU  - Ernst, Daniela
AU  - Van Veldhoven, Paul P
AU  - Alamoudi, Ashraf
AU  - Latz, Eicke
AU  - Othman, Alaa
AU  - Kuerschner, Lars
AU  - Hornemann, Thorsten
AU  - Bradke, Frank
AU  - Thiele, Christoph
AU  - Penno, Anke
TI  - Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.
JO  - Journal of lipid research
VL  - 58
IS  - 1
SN  - 0022-2275
CY  - Bethesda, Md.
PB  - ASBMB
M1  - DZNE-2020-05312
SP  - 42-59
PY  - 2017
AB  - 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.
KW  - Animals
KW  - Diabetes Mellitus, Type 2: blood
KW  - Diabetes Mellitus, Type 2: pathology
KW  - Diabetic Neuropathies: blood
KW  - Diabetic Neuropathies: pathology
KW  - Hereditary Sensory and Autonomic Neuropathies: blood
KW  - Hereditary Sensory and Autonomic Neuropathies: pathology
KW  - Humans
KW  - Lipids: blood
KW  - Male
KW  - Mitochondria: drug effects
KW  - Mitochondria: metabolism
KW  - Mitochondria: pathology
KW  - Oxidoreductases: metabolism
KW  - Peripheral Nerves: metabolism
KW  - Peripheral Nerves: pathology
KW  - Sphingolipids: blood
KW  - Sphingolipids: chemical synthesis
KW  - Sphingolipids: pharmacology
KW  - Lipids (NLM Chemicals)
KW  - Sphingolipids (NLM Chemicals)
KW  - Oxidoreductases (NLM Chemicals)
KW  - dihydroceramide desaturase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27881717
C2  - pmc:PMC5234710
DO  - DOI:10.1194/jlr.M068676
UR  - https://pub.dzne.de/record/138990
ER  -