Journal Article

DZNE-2020-05312

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.

Alecu, I. ; Tedeschi, A.DZNE* ; Behler, N. ; Wunderling, K. ; Lamberz, C.DZNE* ; Lauterbach, M. A. R. ; Gaebler, A. ; Ernst, D. ; Van Veldhoven, P. P. ; Alamoudi, A.DZNE* ; Latz, E. ; Othman, A. ; Kuerschner, L. ; Hornemann, T. ; Bradke, F.DZNE* ; Thiele, C. ; Penno, A. (Corresponding author)

2017
ASBMB Bethesda, Md.

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Please use a persistent id in citations: doi:10.1194/jlr.M068676

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.

Keyword(s): Animals (MeSH) ; Diabetes Mellitus, Type 2: blood (MeSH) ; Diabetes Mellitus, Type 2: pathology (MeSH) ; Diabetic Neuropathies: blood (MeSH) ; Diabetic Neuropathies: pathology (MeSH) ; Hereditary Sensory and Autonomic Neuropathies: blood (MeSH) ; Hereditary Sensory and Autonomic Neuropathies: pathology (MeSH) ; Humans (MeSH) ; Lipids: blood (MeSH) ; Male (MeSH) ; Mitochondria: drug effects (MeSH) ; Mitochondria: metabolism (MeSH) ; Mitochondria: pathology (MeSH) ; Oxidoreductases: metabolism (MeSH) ; Peripheral Nerves: metabolism (MeSH) ; Peripheral Nerves: pathology (MeSH) ; Sphingolipids: blood (MeSH) ; Sphingolipids: chemical synthesis (MeSH) ; Sphingolipids: pharmacology (MeSH) ; Lipids ; Sphingolipids ; Oxidoreductases ; dihydroceramide desaturase

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Contributing Institute(s):

1. Axon Growth and Regeneration (AG Bradke)
2. Cryo-electron microscopy and tomography (AG Alamoudi)

Research Program(s):

1. 341 - Molecular Signaling (POF3-341) (POF3-341)

Appears in the scientific report 2017

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Database coverage:
; ; ; ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; IF >= 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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