Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

Ji Na Kong, Zhihui Zhu, Yutaka Itokazu, Guanghu Wang, Michael B. Dinkins, Liansheng Zhong, Hsuan Pei Lin, Ahmed Elsherbini, Silvia Leanhart, Xue Jiang, Haiyan Qin, Wenbo Zhi, Stefka D. Spassieva, Erhard Bieberich

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

We reported that amyloid β peptide (Aβ 42 ) activated neutral SMase 2 (nSMase2), thereby increasing the concentration of the sphingolipid ceramide in astrocytes. Here, we show that Aβ 42 induced mitochondrial fragmentation in wild-type astrocytes, but not in nSMase2-deficient cells or astrocytes treated with fumonisin B1 (FB1), an inhibitor of ceramide synthases. Unexpectedly, ceramide depletion was concurrent with rapid movements of mitochondria, indicating an unknown function of ceramide for mitochondria. Using immunocytochemistry and super-resolution microscopy, we detected ceramide-enriched and mitochondriaassociated membranes (CEMAMs) that were codistributed with microtubules. Interaction of ceramide with tubulin was confirmed by cross-linking to N-[9-(3-pent-4-ynyl-3-Hdiazirine- 3-yl)-nonanoyl]-D-erythro-sphingosine (pacFACer), a bifunctional ceramide analog, and binding of tubulin to ceramide-linked agarose beads. Ceramide-associated tubulin (CAT) translocated from the perinuclear region to peripheral CEMAMs and mitochondria, which was prevented in nSMase2-deficient or FB1-treated astrocytes. Proximity ligation and coimmunoprecipitation assays showed that ceramide depletion reduced association of tubulin with voltage-dependent anion channel 1 (VDAC1), an interaction known to block mitochondrial ADP/ATP transport. Ceramidedepleted astrocytes contained higher levels of ATP, suggesting that ceramide-induced CAT formation leads to VDAC1 closure, thereby reducing mitochondrial ATP release, and potentially motility and resistance to Aβ 42 . Our data also indicate that inhibiting ceramide generation may protect mitochondria in Alzheimer's disease.

Original languageEnglish
Pages (from-to)488-506
Number of pages19
JournalJournal of Lipid Research
Volume59
Issue number3
DOIs
StatePublished - 2018

Bibliographical note

Funding Information:
This work was supported by National Institute on Aging Grant R01AG034389, National Institute of Neurological Disorders and Stroke Grant R01NS095215, the National Science Foundation, and Division of Molecular and Cellular Biosciences Grant 1615874. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Manuscript received 15 November 2017 and in revised form 8 January 2018. Published, JLR Papers in Press, January 10, 2018 DOI https://doi.org/10.1194/jlr.M081877

Funding Information:
This work was supported by National Institute on Aging Grant R01AG034389, National Institute of Neurological Disorders and Stroke Grant R01NS095215, the National Science Foundation, and Division of Molecular and Cellular Biosciences Grant 1615874. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.

Keywords

  • Adenosine 5′-triphosphate
  • Mitochondria-associated membranes
  • Sphingolipids

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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