Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes[S]
| Autor: | Stefka D. Spassieva, Xue Jiang, Ahmed Elsherbini, Yutaka Itokazu, Wenbo Zhi, Liansheng Zhong, Haiyan Qin, Silvia Leanhart, Michael B. Dinkins, Hsuan Pei Lin, Erhard Bieberich, Ji Na Kong, Guanghu Wang, Zhihui Zhu |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Ceramide QD415-436 Mitochondrion Ceramides Biochemistry 03 medical and health sciences chemistry.chemical_compound Endocrinology Adenosine Triphosphate Microtubule Alzheimer Disease Tubulin Humans adenosine 5′-triphosphate Research Articles Fumonisin B1 biology ATP transport Chemistry Cell Biology Sphingolipid Cell biology Mitochondria 030104 developmental biology Astrocytes Mitochondrial Membranes biology.protein VDAC1 sphingolipids • mitochondria-associated membranes |
| Zdroj: | Journal of Lipid Research, Vol 59, Iss 3, Pp 488-506 (2018) |
| Popis: | 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 mitochondria-associated 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-H-diazirine-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. Ceramide-depleted 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. |
| Databáze: | OpenAIRE |
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