期刊
JOURNAL OF LIPID RESEARCH
卷 59, 期 3, 页码 488-506出版社
ELSEVIER
DOI: 10.1194/jlr.M081877
关键词
adenosine 5 '-triphosphate; sphingolipids; mitochondria-associated membranes
资金
- National Institute on Aging [R01AG034389]
- National Institute of Neurological Disorders and Stroke [R01NS095215]
- National Science Foundation
- Division of Molecular and Cellular Biosciences Grant [1615874]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS095215] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG034389] Funding Source: NIH RePORTER
We reported that amyloid beta peptide (A beta(42)) activated neutral SMase 2 (nSMase2), thereby increasing the concentration of the sphingolipid ceramide in astrocytes. Here, we show that A beta(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 A beta(42). Our data also indicate that inhibiting ceramide generation may protect mitochondria in Alzheimer's disease.
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