Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

Irina Alecu; Andrea Tedeschi; Natascha Behler; Klaus Wunderling; Christian Lamberz; Mario A.R. Lauterbach; Anne Gaebler; Daniela Ernst; Paul P. Van Veldhoven; Ashraf Al-Amoudi; Eicke Latz; Alaa Othman; Lars Kuerschner; Thorsten Hornemann; Frank Bradke; Christoph Thiele; And Anke Penno

doi:10.1194/jlr.M068676

Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

Irina Alecu, Andrea Tedeschi, Natascha Behler, Klaus Wunderling, Christian Lamberz, Mario A.R. Lauterbach, Anne Gaebler, Daniela Ernst, Paul P. Van Veldhoven, Ashraf Al-Amoudi, Eicke Latz, Alaa Othman, Lars Kuerschner, Thorsten Hornemann, Frank Bradke, Christoph Thiele, And Anke Penno^*

^*Corresponding author for this work

Institute of Experimental Dermatology

74 Citations (Scopus)

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.-Alecu, I., A. Tedeschi, N. Behler, K. Wunderling, C. Lamberz, M. A. R. Lauterbach, A. Gaebler, D. Ernst, P. P. Van Veldhoven, A. Al-Amoudi, E. Latz, A. Othman, L. Kuerschner, T. Hornemann, F. Bradke, C. Thiele, and A. Penno. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.

Original language	English
Journal	Journal of Lipid Research
Volume	58
Issue number	1
Pages (from-to)	42-59
Number of pages	18
ISSN	0022-2275
DOIs	https://doi.org/10.1194/jlr.M068676
Publication status	Published - 01.01.2017

Funding

M.A.R.L. was supported by Deutsche Forschungsgemeinschaft (DFG) Grant SFB1123. I.A., T.H., D.E., and A.O. were supported by the 7th Framework Program of the European Commission "RESOLVE" Project 305707; Swiss National Foundation SNF Project 31003A-153390/1; the Hurka Foundation; the Novartis Foundation; and the Rare Disease Initiative Zurich ("radiz," Clinical Research Priority Program for Rare Diseases, University of Zurich). F.B. is supported by the DFG, International Research in Paraplegia, and Wings for Life. C.T., A.G., L.K., K.W., E.L., and A.P. were supported by DFG Grants SFB645 and TRR83, and A.A.-A. and C.L. also were supported by DFG Grant TRR83

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1194/jlr.M068676

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Alecu, I., Tedeschi, A., Behler, N., Wunderling, K., Lamberz, C., Lauterbach, M. A. R., Gaebler, A., Ernst, D., Van Veldhoven, P. P., Al-Amoudi, A., Latz, E., Othman, A., Kuerschner, L., Hornemann, T., Bradke, F., Thiele, C., & Penno, A. A. (2017). Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction. Journal of Lipid Research, 58(1), 42-59. https://doi.org/10.1194/jlr.M068676

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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.-Alecu, I., A. Tedeschi, N. Behler, K. Wunderling, C. Lamberz, M. A. R. Lauterbach, A. Gaebler, D. Ernst, P. P. Van Veldhoven, A. Al-Amoudi, E. Latz, A. Othman, L. Kuerschner, T. Hornemann, F. Bradke, C. Thiele, and A. Penno. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.",

author = "Irina Alecu and Andrea Tedeschi and Natascha Behler and Klaus Wunderling and Christian Lamberz and Lauterbach, \{Mario A.R.\} and Anne Gaebler and Daniela Ernst and \{Van Veldhoven\}, \{Paul P.\} and Ashraf Al-Amoudi and Eicke Latz and Alaa Othman and Lars Kuerschner and Thorsten Hornemann and Frank Bradke and Christoph Thiele and Penno, \{And Anke\}",

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Alecu, I, Tedeschi, A, Behler, N, Wunderling, K, Lamberz, C, Lauterbach, MAR, Gaebler, A, Ernst, D, Van Veldhoven, PP, Al-Amoudi, A, Latz, E, Othman, A, Kuerschner, L, Hornemann, T, Bradke, F, Thiele, C & Penno, AA 2017, 'Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction', Journal of Lipid Research, vol. 58, no. 1, pp. 42-59. https://doi.org/10.1194/jlr.M068676

TY - JOUR

T1 - Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

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 - Al-Amoudi, Ashraf

AU - Latz, Eicke

AU - Othman, Alaa

AU - Kuerschner, Lars

AU - Hornemann, Thorsten

AU - Bradke, Frank

AU - Thiele, Christoph

AU - Penno, And Anke

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.-Alecu, I., A. Tedeschi, N. Behler, K. Wunderling, C. Lamberz, M. A. R. Lauterbach, A. Gaebler, D. Ernst, P. P. Van Veldhoven, A. Al-Amoudi, E. Latz, A. Othman, L. Kuerschner, T. Hornemann, F. Bradke, C. Thiele, and A. Penno. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.

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.-Alecu, I., A. Tedeschi, N. Behler, K. Wunderling, C. Lamberz, M. A. R. Lauterbach, A. Gaebler, D. Ernst, P. P. Van Veldhoven, A. Al-Amoudi, E. Latz, A. Othman, L. Kuerschner, T. Hornemann, F. Bradke, C. Thiele, and A. Penno. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction.

UR - https://www.scopus.com/pages/publications/85009902090

U2 - 10.1194/jlr.M068676

DO - 10.1194/jlr.M068676

M3 - Journal articles

C2 - 27881717

AN - SCOPUS:85009902090

SN - 0022-2275

VL - 58

SP - 42

EP - 59

JO - Journal of Lipid Research

JF - Journal of Lipid Research

IS - 1

ER -

Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction

Abstract

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