S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health
Astrocytes are critical players in brain health and disease. Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival, and migration. It was shown to be crucial for brain development. Its absence is embryonically l...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/5/4581 |
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| author | Shah Alam Sumaiya Yasmeen Afsar Gerhild Van Echten-Deckert |
| author_facet | Shah Alam Sumaiya Yasmeen Afsar Gerhild Van Echten-Deckert |
| author_sort | Shah Alam |
| collection | DOAJ |
| description | Astrocytes are critical players in brain health and disease. Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival, and migration. It was shown to be crucial for brain development. Its absence is embryonically lethal, affecting, inter alia, the anterior neural tube closure. However, an excess of S1P due to mutations in S1P-lyase (SGPL1), the enzyme responsible for its constitutive removal, is also harmful. Of note, the gene <i>SGPL1</i> maps to a region prone to mutations in several human cancers and also in S1P-lyase insufficiency syndrome (SPLIS) characterized by several symptoms, including peripheral and central neurological defects. Here, we investigated the impact of S1P on astrocytes in a mouse model with the neural−targeted ablation of SGPL1. We found that SGPL1 deficiency, and hence the accumulation of its substrate, S1P, causes the elevated expression of glycolytic enzymes and preferentially directs pyruvate into the tricarboxylic acid (TCA) cycle through its receptors (S1PR<sub>2,4</sub>). In addition, the activity of TCA regulatory enzymes was increased, and consequently, so was the cellular ATP content. The high energy load activates the mammalian target of rapamycin (mTOR), thus keeping astrocytic autophagy in check. Possible consequences for the viability of neurons are discussed. |
| first_indexed | 2024-03-11T07:23:07Z |
| format | Article |
| id | doaj.art-ef392ae8061a48fc82faad5ee9c2d40f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T07:23:07Z |
| publishDate | 2023-02-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ef392ae8061a48fc82faad5ee9c2d40f2023-11-17T07:50:27ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01245458110.3390/ijms24054581S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain HealthShah Alam0Sumaiya Yasmeen Afsar1Gerhild Van Echten-Deckert2LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53115 Bonn, GermanyLIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53115 Bonn, GermanyLIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53115 Bonn, GermanyAstrocytes are critical players in brain health and disease. Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival, and migration. It was shown to be crucial for brain development. Its absence is embryonically lethal, affecting, inter alia, the anterior neural tube closure. However, an excess of S1P due to mutations in S1P-lyase (SGPL1), the enzyme responsible for its constitutive removal, is also harmful. Of note, the gene <i>SGPL1</i> maps to a region prone to mutations in several human cancers and also in S1P-lyase insufficiency syndrome (SPLIS) characterized by several symptoms, including peripheral and central neurological defects. Here, we investigated the impact of S1P on astrocytes in a mouse model with the neural−targeted ablation of SGPL1. We found that SGPL1 deficiency, and hence the accumulation of its substrate, S1P, causes the elevated expression of glycolytic enzymes and preferentially directs pyruvate into the tricarboxylic acid (TCA) cycle through its receptors (S1PR<sub>2,4</sub>). In addition, the activity of TCA regulatory enzymes was increased, and consequently, so was the cellular ATP content. The high energy load activates the mammalian target of rapamycin (mTOR), thus keeping astrocytic autophagy in check. Possible consequences for the viability of neurons are discussed.https://www.mdpi.com/1422-0067/24/5/4581sphingosine 1-phosphate (S1P)S1P-lyase (SGPL1)SPLISglucose metabolismautophagy |
| spellingShingle | Shah Alam Sumaiya Yasmeen Afsar Gerhild Van Echten-Deckert S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health International Journal of Molecular Sciences sphingosine 1-phosphate (S1P) S1P-lyase (SGPL1) SPLIS glucose metabolism autophagy |
| title | S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health |
| title_full | S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health |
| title_fullStr | S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health |
| title_full_unstemmed | S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health |
| title_short | S1P Released by SGPL1-Deficient Astrocytes Enhances Astrocytic ATP Production via S1PR<sub>2,4</sub>, Thus Keeping Autophagy in Check: Potential Consequences for Brain Health |
| title_sort | s1p released by sgpl1 deficient astrocytes enhances astrocytic atp production via s1pr sub 2 4 sub thus keeping autophagy in check potential consequences for brain health |
| topic | sphingosine 1-phosphate (S1P) S1P-lyase (SGPL1) SPLIS glucose metabolism autophagy |
| url | https://www.mdpi.com/1422-0067/24/5/4581 |
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