Sirt1 promotes tissue regeneration in zebrafish through regulating the mitochondrial unfolded protein response

The mitochondrial unfolded protein response (UPR^mt) is an organellar stress signaling pathway that functions to detect and restore disruption of mitochondrial proteostasis. The UPR^mt is involved in a wide range of physiological and disease conditions, including aging, stem cell maintenance, innate immunity, neurodegeneration, and cancer. Here we report that the UPR^mt is integral to zebrafish fin regeneration. Taking advantage of a novel zebrafish UPR^mt reporter, we observed that UPR^mt activation occurs in regenerating fin tissue shortly after injury. Through chemical and genetic approaches, we discovered that the Sirt1-UPR^mt pathway, best known for its role in promoting lifespan extension, is crucial for fin regeneration. The metabolism of NAD⁺ is an important contributor to Sirt1 activity in this context. We propose that Sirt1 activation induces mitochondrial biogenesis in injured fin tissue, which leads to UPR^mt activation and promotes tissue regeneration.