P2RY11–SIRT1–PGC-1α–dependent mitochondrial redox and bioenergetic regulation of macrophages drives fin regeneration in zebrafish

Abstract

Abstract Background Tissue regeneration is an energy-intensive process that requires coordinated mitochondrial bioenergetics and redox homeostasis. Extracellular ATP is rapidly released after tissue injury, but how ATP-derived signals support regenerative repair remains incompletely understood. Here, we investigated whether the purinergic receptor P2RY11 regulates macrophage mitochondrial metabolism and thereby promotes tissue regeneration. Methods Using zebrafish caudal fin regeneration as an in vivo model, we examined regenerative outgrowth, cell proliferation, macrophage accumulation and migration, mitochondrial function, redox status, and metabolic gene expression in p2ry11 -deficient larvae. Genetic ablation and pharmacological inhibition of P2RY11 were combined with macrophage depletion and pathway rescue experiments targeting the SIRT1–PGC-1α axis and PPARγ signaling. Results Loss or inhibition of p2ry11 markedly impaired caudal fin regeneration, reduced injury-induced cell proliferation, and decreased macrophage migratory capacity and accumulation at the wound site. Mechanistically, p2ry11 deficiency disrupted systemic mitochondrial metabolic and redox homeostasis, as evidenced by a reduced NAD⁺/NADH ratio and decreased PGC-1α expression. Importantly, cell-resolved analyses further revealed mitochondrial depolarization, increased mtROS accumulation, and reduced ATP levels specifically in injury-associated macrophages. Systemic antioxidant defense was also compromised, with reduced CAT and SOD activities, decreased GSH content, and suppressed expression of antioxidant-related genes. Pharmacological activation of SIRT1 or PGC-1α restored mitochondrial redox and bioenergetic function and rescued fin regeneration, whereas inhibition of PGC-1α abolished the SIRT1-mediated rescue. Importantly, macrophage depletion eliminated the regenerative benefits of SIRT1–PGC-1α activation, demonstrating that macrophages are essential effectors of this pathway. Treatment with the clinically approved PPARγ agonist rosiglitazone similarly restored macrophage mitochondrial function and rescued regeneration, whereas activation of canonical cAMP–PKA or PKC signaling failed to improve regenerative outcomes. Conclusions These findings identify P2RY11 as an injury-responsive metabolic regulator that promotes tissue regeneration by sustaining macrophage mitochondrial bioenergetics and redox balance through the NAD + –SIRT1–PGC-1α axis. Targeting macrophage mitochondrial fitness may provide a therapeutic strategy for enhancing regenerative repair.

The authors' abstract, as published at the source. Cell Communication and Signaling, 2026 · DOI ↗