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 journalArticle

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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 (US)
Pages (from-to)488-506
Number of pages19
JournalJournal of Lipid Research
Volume59
Issue number3
DOIs
StatePublished - Jan 1 2018

Fingerprint

Ceramides
Astrocytes
Adenosine Triphosphate
Tubulin
Mitochondria
Voltage-Dependent Anion Channel 1
Membranes
Sphingolipids
Amyloid
Microtubules
Sepharose
Adenosine Diphosphate
Ligation
Microscopy
Assays
Microscopic examination
Alzheimer Disease
Immunohistochemistry

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Kong, J. N., Zhu, Z., Itokazu, Y., Wang, G., Dinkins, M. B., Zhong, L., ... Bieberich, E. (2018). Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes. Journal of Lipid Research, 59(3), 488-506. https://doi.org/10.1194/jlr.M081877

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes. / Kong, Ji Na; Zhu, Zhihui; Itokazu, Yutaka; Wang, Guanghu; Dinkins, Michael B.; Zhong, Liansheng; Lin, Hsuan Pei; Elsherbini, Ahmed; Leanhart, Silvia; Jiang, Xue; Qin, Haiyan; Zhi, Wenbo; Spassieva, Stefka D.; Bieberich, Erhard.

In: Journal of Lipid Research, Vol. 59, No. 3, 01.01.2018, p. 488-506.

Research output: Contribution to journalArticle

Kong, JN, Zhu, Z, Itokazu, Y, Wang, G, Dinkins, MB, Zhong, L, Lin, HP, Elsherbini, A, Leanhart, S, Jiang, X, Qin, H, Zhi, W, Spassieva, SD & Bieberich, E 2018, 'Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes', Journal of Lipid Research, vol. 59, no. 3, pp. 488-506. https://doi.org/10.1194/jlr.M081877
Kong, Ji Na ; Zhu, Zhihui ; Itokazu, Yutaka ; Wang, Guanghu ; Dinkins, Michael B. ; Zhong, Liansheng ; Lin, Hsuan Pei ; Elsherbini, Ahmed ; Leanhart, Silvia ; Jiang, Xue ; Qin, Haiyan ; Zhi, Wenbo ; Spassieva, Stefka D. ; Bieberich, Erhard. / Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes. In: Journal of Lipid Research. 2018 ; Vol. 59, No. 3. pp. 488-506.
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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.",
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AU - Kong, Ji Na

AU - Zhu, Zhihui

AU - Itokazu, Yutaka

AU - Wang, Guanghu

AU - Dinkins, Michael B.

AU - Zhong, Liansheng

AU - Lin, Hsuan Pei

AU - Elsherbini, Ahmed

AU - Leanhart, Silvia

AU - Jiang, Xue

AU - Qin, Haiyan

AU - Zhi, Wenbo

AU - Spassieva, Stefka D.

AU - Bieberich, Erhard

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