Macrophage Mitochondria Powered by P2RY11 Drive Fin Regeneration in Zebrafish

Zebrafish can regrow severed fins with remarkable efficiency, and a new study points to an unexpected engine behind that ability: the mitochondria of macrophages, regulated by a purinergic signaling pathway. Researchers report that the ATP-sensing receptor P2RY11 sustains macrophage mitochondrial bioenergetics and redox balance through the NAD+–SIRT1–PGC-1α axis, and that this pathway is required for caudal fin regeneration in zebrafish larvae.

The work, published in Cell Communication and Signaling, addresses a long-standing question in regenerative biology. Tissue repair is an energy-intensive process, and extracellular ATP is rapidly released after injury, yet how ATP-derived signals actually support regenerative repair has remained incompletely understood. The team set out to test whether P2RY11, a receptor for these extracellular purine signals, regulates macrophage mitochondrial metabolism in a way that promotes tissue regrowth.

Using zebrafish caudal fin regeneration as an in vivo model, the researchers examined regenerative outgrowth, cell proliferation, macrophage accumulation and migration, mitochondrial function, redox status, and metabolic gene expression in p2ry11-deficient larvae. They combined genetic ablation and pharmacological inhibition of P2RY11 with macrophage depletion and rescue experiments targeting the SIRT1–PGC-1α axis and PPARγ signaling.

The results were striking. Loss or inhibition of p2ry11 markedly impaired caudal fin regeneration, reduced injury-induced cell proliferation, and decreased the migratory capacity of macrophages and their accumulation at the wound site. In other words, when the receptor was missing, both the cellular responders and the regenerative output faltered together.

Mechanistically, p2ry11 deficiency disrupted systemic mitochondrial metabolic and redox homeostasis, as shown by a reduced NAD+/NADH ratio and decreased PGC-1α expression. Cell-resolved analyses went further, revealing mitochondrial depolarization, increased accumulation of mitochondrial reactive oxygen species, and reduced ATP levels specifically in injury-associated macrophages. Systemic antioxidant defense was also compromised, with reduced catalase and superoxide dismutase activities, decreased glutathione content, and suppressed expression of antioxidant-related genes.

The rescue experiments provided the strongest evidence for the pathway. 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. Critically, macrophage depletion eliminated the regenerative benefits of SIRT1–PGC-1α activation, demonstrating that macrophages are essential effectors of this pathway rather than incidental bystanders.

The team also tested a translational angle. Treatment with rosiglitazone, a clinically approved PPARγ agonist, similarly restored macrophage mitochondrial function and rescued regeneration. By contrast, activation of canonical cAMP–PKA or PKC signaling failed to improve regenerative outcomes, suggesting the benefit runs specifically through the metabolic axis rather than generic purinergic downstream signaling.

The authors conclude that P2RY11 acts 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. They suggest that targeting macrophage mitochondrial fitness may offer a therapeutic strategy for enhancing regenerative repair.

Several caveats deserve emphasis. The findings come from zebrafish larvae, an established but non-mammalian regeneration model, and the published version notes it is an accepted manuscript shared early, subject to further edits before the final Version of Record. The rosiglitazone result is a proof of mechanism in fish, not a demonstration of clinical benefit in humans. Nevertheless, the study adds a concrete molecular link between injury-released ATP, immune-cell metabolism, and the restoration of lost tissue, an intersection that regenerative biologists have been probing for years.

Subject of Research: P2RY11-dependent macrophage mitochondrial regulation of fin regeneration in zebrafish

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

Article References: Zhou, Y., Li, L., Hao, H., Zhang, Z., Zhao, L., Wang, L., Ma, Y., & Chen, D. (2026). P2RY11–SIRT1–PGC-1α–dependent mitochondrial redox and bioenergetic regulation of macrophages drives fin regeneration in zebrafish. Cell Communication and Signaling. https://doi.org/10.1186/s12964-026-03328-7

Image Credits: AI Generated

DOI: 10.1186/s12964-026-03328-7

Keywords: P2RY11, SIRT1, PGC-1α, macrophages, mitochondria, zebrafish, fin regeneration, NAD+, redox homeostasis, PPARγ, rosiglitazone, purinergic signaling