Mitochondrial P2X7 Receptor Localization Modulates Energy Metabolism Enhancing Physical Performance

Sarti, Alba Clara; Vultaggio-Poma, Valentina; Falzoni, Simonetta; Missiroli, Sonia; Giuliani, Anna; Boldrini, Paola; Bonora, Massimo; Faita, Francesco; Lascio, Nicole Di; Kusmic, Claudia; Solini, Anna; Novello, Salvatore; Morari, Michele; Rossato, Marco; Wieckowski, Mariusz R.; Giorgi, Carlotta; Pinton, Paolo; Virgilio, Francesco Di

doi:10.1093/function/zqab005

Cited by 39 publications

(55 citation statements)

References 53 publications

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“…Our results suggest that the signal from the NPCs and neurons is of intracellular origin, while the signal detected from microglia-like cells clearly outlined the whole surface of the cell, indicating membranous expression of the receptor ( Figures 6A,B ). The intracellular localization of the P2X7R has been reported by others ( Gu et al, 2000 ; Sarti et al, 2021 ). Therefore, to further investigate the localization of the P2X7R on our cells, cell surface protein biotinylation and isolation assay was performed.…”

Section: Resultssupporting

confidence: 73%

Detection and Functional Evaluation of the P2X7 Receptor in hiPSC Derived Neurons and Microglia-Like Cells

Francistiová

Vörös

Lovász

et al. 2022

Front. Mol. Neurosci.

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A large body of evidence suggests the involvement of the ATP-gated purinergic receptor P2X7 (P2X7R) in neurodegenerative diseases, including Alzheimer’s disease. While it is well-described to be present and functional on microglia cells contributing to inflammatory responses, some reports suggest a neuronal expression of the receptor as well. Here, we present experimental results showing P2X7 receptors to be expressed on human hiPSC-derived microglia-like cells, hiPSC-derived neuronal progenitors and hiPSC-derived matured neuronal cells. By applying cell surface protein detection assays, we show that P2X7R is not localized on the cell membrane, despite being detected in neuronal cells and thus may not be available for directly mediating neurotoxicity. On hiPSC-derived microglia-like cells, a clear membranous expression was detected. Additionally, we have not observed differences in P2X7R functions between control and familial Alzheimer’s disease patient-derived neuronal cells. Functional assays employing a P2X7R antagonist JNJ 47965567 confirm these findings by showing P2X7R-dependent modulation of microglia-like cells viability upon treatment with P2X7R agonists ATP and BzATP, while the same effect was absent from neuronal cells. Since the majority of P2X7R research was done on rodent models, our work on human hiPSC-derived cells presents a valuable contribution to the field, extending the work on animal models to the human cellular system and toward clinical translation.

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Section: Resultssupporting

confidence: 73%

Detection and Functional Evaluation of the P2X7 Receptor in hiPSC Derived Neurons and Microglia-Like Cells

Francistiová

Vörös

Lovász

et al. 2022

Front. Mol. Neurosci.

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“…The P2X7 receptor participates in regulation of mitochondrial functions, and the tone of ATP stimulation is crucial for determining downstream events. While tonic stimulation has a stabilizing effect on mitochondrial homeostasis, resulting in increased mitochondrial potential (Δψm) and oxidative phosphorylation efficiency; overstimulation has a killing effect, resulting in decreased Δψm, mitochondrial fragmentation and cell death [ 17 , 18 ]. Therefore, the expected effect of a tonic eATP (extracellular ATP) stimulation of P2X7 receptor in the tumor microenvironment is a combination of both increased glycolytic rate and oxidative phosphorylation efficiency, which contributes to ATP synthesis and anabolic responses [ 19 ].…”

Section: P2x7 Receptor Relevance In Metabolismmentioning

confidence: 99%

“…Also, P2X7 receptor-induced effects on Δψm may play a role in determining stem cell fate, as well as tumorigenic potential. Indeed, Δψm is reduced in several cell types lacking P2X receptors, including HEK293 cells, human and mouse embryonal fibroblasts and microglia [ 17 , 18 , 67 ].…”

Section: P2x7 Receptor Relevance In Metabolismmentioning

confidence: 99%

“…Following, it drives upregulation of glycolytic-related enzymes, such as pyruvate dehydrogenase kinase-1 (PDHK-1) [ 72 ], a similar response to that observed in stem cells in the presence of glucose [ 62 ], and others, as glyceraldehyde 3-phosphate dehydrogenase (G3PDH), phosphofructokinase (PFK), and pyruvate kinase M2 (PKM2) [ 72 ]. Despite glycolytic improvements, the P2X7R is also related to increased expression of glucose transporters (GLUT) [ 72 , 73 ], increasing glucose uptake and oxidative phosphorylation, matched to higher expression of mitochondrial complex 1 and potential (Δψm), as well as mitochondria number [ 18 ] and increased glycogen storages through GSK3β phosphorylation [ 20 ]. Altogether, these metabolic shifts make cells highly capable of surviving in deprivation conditions and enhance the tumorigenic potential of cancer cells (Created with BioRender.com).…”

Section: Figurementioning

confidence: 99%

“…The receptor tonic stimulation increases mitochondrial potential (Δψm), the glycolytic rate, glycogen storage and oxidative phosphorylation efficiency. On the other hand, its overstimulation is detrimental for cells, resulting in decreased Δψm, mitochondrial fragmentation and cell death [ 17 , 18 , 19 , 20 ]. Besides, the absence of the P2X7 receptor reduces mRNA and protein expression of fatty acid metabolism key enzymes, such as FASN and acetyl-CoA carboxylase (ACC), and increases serum triglyceride and cholesterol levels, glucose intolerance and insulin resistance, which decreases stemness, proliferation, survival, invasiveness and therapeutic resistance [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor

Rabelo

Arnaud-Sampaio

Adinolfi

et al. 2021

Cells

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The heterogeneity of tumor cell mass and the plasticity of cancer cell phenotypes in solid tumors allow for the insurgence of resistant and metastatic cells, responsible for cancer patients’ clinical management’s main challenges. Among several factors that are responsible for increased cancer aggression, metabolic reprogramming is recently emerging as an ultimate cancer hallmark, as it is central for cancer cell survival and self-renewal, metastasis and chemoresistance. The P2X7 receptor, whose expression is upregulated in many solid and hematological malignancies, is also emerging as a good candidate in cancer metabolic reprogramming and the regulation of stem cell proliferation and differentiation. Metabostemness refers to the metabolic reprogramming of cancer cells toward less differentiated (CSCs) cellular states, and we believe that there is a strong correlation between metabostemness and P2X7 receptor functions in oncogenic processes. Here, we summarize important aspects of P2X7 receptor functions in normal and tumor tissues as well as essential aspects of its structure, regulation, pharmacology and its clinical use. Finally, we review current knowledge implicating P2X7 receptor functions in cancer-related molecular pathways, in metabolic reprogramming and in metabostemness.

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The P2X7 purinergic receptor in intervertebral disc degeneration

Penolazzi

Bergamin

Lambertini

et al. 2021

Journal Cellular Physiology

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Mechanisms involved in the development of intervertebral disc (IVD) degeneration are only partially known, thus making the implementation of effective therapies very difficult. In this study, we investigated P2X7 purinergic receptor (P2X7R), NLRP3 inflammasome, and interleukin (IL)‐1β expression in IVD specimens at different stages of disease progression, and during the in vitro dedifferentiation process of the primary cells derived thereof. We found that P2X7R, NLRP3, and IL‐1β expression was higher in the IVD samples at a more advanced stage of degeneration and in the expanded IVD cells in culture which partially recapitulated the in vivo degeneration process. In IVD cells, the P2X7R showed a striking nuclear localization, while NLRP3 was mainly cytoplasmic. Stimulation with the semiselective P2X7R agonist benzoyl ATP together with lipopolysaccharide treatment triggered P2X7R transfer to the cytoplasm and P2X7R/NLRP3 colocalization. Taken together, these findings support pathophysiological evidence that the degenerated disc is a highly inflamed microenvironment and highlight the P2X7R/NLRP3 axis as a suitable therapeutic target. The immunohistochemical analysis and the assessment of subcellular localization revealed a substantial expression of P2X7R also in normal disc tissue. This gives us the opportunity to contribute to the few studies performed in natively expressed human P2X7R so far, and to understand the possible physiological ATP‐mediated P2X7R homeostasis signaling. Therefore, collectively, our findings may offer a new perspective and pave the way for the exploration of a role of P2X7R‐mediated purinergic signaling in IVD metabolism that goes beyond its involvement in inflammation.

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Mitochondrial P2X7 Receptor Localization Modulates Energy Metabolism Enhancing Physical Performance

Cited by 39 publications

References 53 publications

Detection and Functional Evaluation of the P2X7 Receptor in hiPSC Derived Neurons and Microglia-Like Cells

Detection and Functional Evaluation of the P2X7 Receptor in hiPSC Derived Neurons and Microglia-Like Cells

Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor

The P2X7 purinergic receptor in intervertebral disc degeneration

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