Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK
Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demons...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824002084 |
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| author | Renata T. Da Costa Anna Nichenko Matheus M. Perez Malgorzata Tokarska-Schlattner Sheida Kavehmoghaddam Vedangi Hambardikar Ernest R. Scoma Erin L. Seifert Uwe Schlattner Joshua C. Drake Maria E. Solesio |
| author_facet | Renata T. Da Costa Anna Nichenko Matheus M. Perez Malgorzata Tokarska-Schlattner Sheida Kavehmoghaddam Vedangi Hambardikar Ernest R. Scoma Erin L. Seifert Uwe Schlattner Joshua C. Drake Maria E. Solesio |
| author_sort | Renata T. Da Costa |
| collection | DOAJ |
| description | Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demonstrated, via molecular mechanism(s) yet to be fully elucidated. In recent years, a role for polyP in signal transduction, from brain physiology to the bloodstream, has also emerged. Objective: In this manuscript, we explored the intriguing possibility that the effects of polyP on signal transduction could be mechanistically linked to those exerted on bioenergetics. Methods: To conduct our studies, we used a combination of cellular and animal models. Results: Our findings demonstrate for the first time the intimate crosstalk between the levels of polyP and the activation status of the AMPK signaling pathway, via a mechanism involving free phosphate homeostasis. AMPK is a key player in mammalian cell signaling, and a crucial regulator of cellular and mitochondrial homeostasis. Our results show that the depletion of mitochondrial polyP in mammalian cells downregulates the activity of AMPK. Moreover, increased levels of polyP activate AMPK. Accordingly, the genetic downregulation of AMPKF0611 impairs polyP levels in both SH-SY5Y cells and in the brains of female mice. Conclusions: This manuscript sheds new light on the regulation of AMPK and positions polyP as a potent regulator of mammalian cell physiology beyond mere bioenergetics, paving the road for using its metabolism as an innovative pharmacological target in pathologies characterized by dysregulated bioenergetics. |
| format | Article |
| id | doaj-art-b22bd80e8fa949fdbcc127e2f04e075e |
| institution | OA Journals |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-b22bd80e8fa949fdbcc127e2f04e075e2025-08-20T02:27:13ZengElsevierMolecular Metabolism2212-87782025-01-019110207710.1016/j.molmet.2024.102077Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPKRenata T. Da Costa0Anna Nichenko1Matheus M. Perez2Malgorzata Tokarska-Schlattner3Sheida Kavehmoghaddam4Vedangi Hambardikar5Ernest R. Scoma6Erin L. Seifert7Uwe Schlattner8Joshua C. Drake9Maria E. Solesio10Department of Biology, and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USADepartment of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, USADepartment of Biology, and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USAUniversity Grenoble Alpes, Inserm U1055, Laboratory of Fundamental and Applied Bioenergetics, Grenoble, FranceDepartment of Biology, and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USADepartment of Biology, and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USADepartment of Biology, and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USAMitoCare and Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USAUniversity Grenoble Alpes, Inserm U1055, Laboratory of Fundamental and Applied Bioenergetics, Grenoble, FranceDepartment of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, USADepartment of Biology, and Center for Computational and Integrative Biology, Rutgers University, Camden, NJ, USA; Corresponding author. Rutgers University, 201 Broadway, Camden, NJ, 08103, USA. Tel.: +1856 225 6395.Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demonstrated, via molecular mechanism(s) yet to be fully elucidated. In recent years, a role for polyP in signal transduction, from brain physiology to the bloodstream, has also emerged. Objective: In this manuscript, we explored the intriguing possibility that the effects of polyP on signal transduction could be mechanistically linked to those exerted on bioenergetics. Methods: To conduct our studies, we used a combination of cellular and animal models. Results: Our findings demonstrate for the first time the intimate crosstalk between the levels of polyP and the activation status of the AMPK signaling pathway, via a mechanism involving free phosphate homeostasis. AMPK is a key player in mammalian cell signaling, and a crucial regulator of cellular and mitochondrial homeostasis. Our results show that the depletion of mitochondrial polyP in mammalian cells downregulates the activity of AMPK. Moreover, increased levels of polyP activate AMPK. Accordingly, the genetic downregulation of AMPKF0611 impairs polyP levels in both SH-SY5Y cells and in the brains of female mice. Conclusions: This manuscript sheds new light on the regulation of AMPK and positions polyP as a potent regulator of mammalian cell physiology beyond mere bioenergetics, paving the road for using its metabolism as an innovative pharmacological target in pathologies characterized by dysregulated bioenergetics.http://www.sciencedirect.com/science/article/pii/S2212877824002084Inorganic polyphosphateMitochondriaMammalian cellsCell signalingAMPKBioenergetics |
| spellingShingle | Renata T. Da Costa Anna Nichenko Matheus M. Perez Malgorzata Tokarska-Schlattner Sheida Kavehmoghaddam Vedangi Hambardikar Ernest R. Scoma Erin L. Seifert Uwe Schlattner Joshua C. Drake Maria E. Solesio Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK Molecular Metabolism Inorganic polyphosphate Mitochondria Mammalian cells Cell signaling AMPK Bioenergetics |
| title | Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK |
| title_full | Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK |
| title_fullStr | Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK |
| title_full_unstemmed | Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK |
| title_short | Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK |
| title_sort | mammalian mitochondrial inorganic polyphosphate polyp and cell signaling crosstalk between polyp and the activity of ampk |
| topic | Inorganic polyphosphate Mitochondria Mammalian cells Cell signaling AMPK Bioenergetics |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824002084 |
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