1. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction
- Author
-
Ashraf Al-Amoudi, Christoph Thiele, Frank Bradke, Anne Gaebler, Christian Lamberz, Andrea Tedeschi, Thorsten Hornemann, Irina Alecu, Klaus Wunderling, Mario A. Lauterbach, Alaa Othman, Paul P. Van Veldhoven, Anke Penno, Lars Kuerschner, Eicke Latz, Natascha Behler, Daniela Ernst, University of Zurich, and Penno, Anke
- Subjects
Male ,0301 basic medicine ,1303 Biochemistry ,Diabetic neuropathy ,blood [Diabetes Mellitus, Type 2] ,pathology [Peripheral Nerves] ,neurons ,Mitochondrion ,Biochemistry ,pathology [Mitochondria] ,metabolism [Peripheral Nerves] ,1307 Cell Biology ,Endocrinology ,Diabetic Neuropathies ,540 Chemistry ,Hereditary sensory and autonomic neuropathy ,blood [Lipids] ,Hereditary Sensory and Autonomic Neuropathies ,Research Articles ,10038 Institute of Clinical Chemistry ,pharmacology [Sphingolipids] ,diabetes ,Chemistry ,lipids/chemistry ,drug effects [Mitochondria] ,blood [Sphingolipids] ,pathology [Diabetic Neuropathies] ,Lipids ,Mitochondria ,1310 Endocrinology ,3. Good health ,Mitochondrial toxicity ,ddc:540 ,Oxidoreductases ,metabolism [Oxidoreductases] ,medicine.medical_specialty ,pathology [Hereditary Sensory and Autonomic Neuropathies] ,pathology [Diabetes Mellitus, Type 2] ,610 Medicine & health ,inborn errors of metabolism ,QD415-436 ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,Peripheral Nerves ,Sphingolipids ,sphingolipids ,blood [Hereditary Sensory and Autonomic Neuropathies] ,Neurotoxicity ,Cell Biology ,Metabolism ,metabolism [Mitochondria] ,medicine.disease ,Sphingolipid ,chemical synthesis [Sphingolipids] ,030104 developmental biology ,Peripheral neuropathy ,Diabetes Mellitus, Type 2 ,dihydroceramide desaturase ,blood [Diabetic Neuropathies] ,chemical synthesis - 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. ispartof: Journal of Lipid Research vol:58 issue:1 pages:42-59 ispartof: location:United States status: published
- Published
- 2017
- Full Text
- View/download PDF