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.