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

doi:10.1194/jlr.m081877

Cited by 40 publications

(56 citation statements)

References 99 publications

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“…Our data is consistent with that from previous studies reporting that the level of Drp-1 is elevated in AD brain and neurons exposed to Aβ in vitro [1,42]. In our previous studies, we showed that Aβ exposure leads to mitochondrial malformation and dysregulation of VDAC1, the main ADP/ATP transporter in the outer mitochondrial membrane the level of which is elevated in AD [14,37,56,59]. Our data is consistent with that from previous studies reporting that Aβ binds to VDAC1 and induces formation of a pro-apoptotic pore [68].…”

Section: Discussionsupporting

confidence: 93%

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Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Elsherbini

Kirov

Dinkins

et al. 2020

acta neuropathol commun

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Amyloid-β (Aβ) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate Aβ neurotoxicity in Alzheimer's disease (AD). We show here that brain tissue and serum from the transgenic mouse model of familial AD (5xFAD) and serum from AD patients contains ceramide-enriched and astrocyte-derived exosomes (termed astrosomes) that are associated with Aβ. In Neuro-2a cells, primary cultured neurons, and human induced pluripotent stem cell-derived neurons, Aβ-associated astrosomes from 5xFAD mice and AD patient serum were specifically transported to mitochondria, induced mitochondrial clustering, and upregulated the fission protein Drp-1 at a concentration corresponding to 5 femtomoles Aβ/L of medium. Aβassociated astrosomes, but not wild type or control human serum exosomes, mediated binding of Aβ to voltagedependent anion channel 1 (VDAC1) and subsequently, activated caspases. Aβ-associated astrosomes induced neurite fragmentation and neuronal cell death, suggesting that association with astrosomes substantially enhances Aβ neurotoxicity in AD and may comprise a novel target for therapy.

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Section: Discussionsupporting

confidence: 93%

“…3e), suggesting that astrosomes delivered Aβ into N2a cells. To further confirm the validity of these results, we used a proximity ligation assay (PLA) for complex formation between ceramide and Aβ in membrane dye PKH67-labeled exosomes taken up by N2a cells [35,37]. Supplemental Fig.…”

Section: Astrosomes Are Taken Up By Neural Cells and Transport Aβ Andmentioning

confidence: 85%

Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Elsherbini

Kirov

Dinkins

et al. 2020

acta neuropathol commun

Self Cite

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“…These ceramide channels bind to, and are regulated by, pro-and antiapoptotic proteins, making this lipid an important player in the induction of apoptosis (187). We also note that increases in the local concentration of ceramide at the MAM "glue" mitochondria to tubulin via the outer membrane protein porin (also called the voltage-dependent anion channel [VDAC]) (155), which regulates mitochondrial transport, subcellular distribution, and division (188).…”

Section: Possible Mechanism Of Oxphos Deficiency In Neurodegenerativementioning

confidence: 96%

“…While the mechanism behind these alterations in glucose metabolism is unknown, the literature discusses several possibilities (155). For instance, AKT activation, a key regulator of glucose metabolism (134), has been shown to be significantly reduced in the substantia nigra of PD patients (156) and in cultured cells exposed to 6-OHDA (157).…”

Section: Possible Mechanism Of Oxphos Deficiency In Neurodegenerativementioning

confidence: 99%

Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas

Area‐Gómez¹,

Guardia‐Laguarta²,

Schon

et al. 2019

Journal of Clinical Investigation

117

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“…A previous in vivo study showed that hypoxia-preconditioned MSCs improve tissue regeneration and blood perfusion in hindlimb ischemia model 25 . Recent studies have also reported the physiological role of sphingosine metabolites, including S1P and ceramide, in hypoxia-induced glycolytic reprogramming and mitochondrial energetic metabolism [26][27][28] . In addition to the regulatory effect exerted by sphingosine metabolites on cell metabolism, S1P priming is an effective strategy to enhance the therapeutic efficacy of MSC treatment via cell trafficking, angiogenesis, and antiinflammation 29 .…”

Section: Introductionmentioning

confidence: 99%

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

et al. 2019

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O-cyclic phytosphingosine-1-phosphate (cP1P) is a novel chemically synthesized sphingosine metabolite derived from phytosphingosine-1-phosphate. Although structurally similar to sphingosine-1-phosphate (S1P), its biological properties in stem cells remain to be reported. We investigated the effect of cP1P on the therapeutic potential of mesenchymal stem cells (MSCs) and their regulatory mechanism. We found that, under hypoxia, cP1P suppressed MSC mitochondrial dysfunction and apoptosis. Metabolic data revealed that cP1P stimulated glycolysis via the upregulation of glycolysis-related genes. cP1P-induced hypoxia-inducible factor 1 alpha (HIF1α) plays a key role for MSC glycolytic reprogramming and transplantation efficacy. The intracellular calcium-dependent PKCα/mammalian target of the rapamycin (mTOR) signaling pathway triggered by cP1P regulated HIF1α translation via S6K1, which is critical for HIF1 activation. Furthermore, the cP1P-activated mTOR pathway induced bicaudal D homolog 1 expression, leading to HIF1α nuclear translocation. In conclusion, cP1P enhances the therapeutic potential of MSC through mTOR-dependent HIF1α translation and nuclear translocation.

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

Cited by 40 publications

References 99 publications

Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Mitochondria, OxPhos, and neurodegeneration: cells are not just running out of gas

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

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