Spiny mouse fibroblasts exhibit a baseline preference for glycolysis and are resilient to oxidative stress across lifespan.

Although metabolism was originally studied across an array of mammals, contemporary metabolic studies moved towards human and mouse cells. A newfound interest in how metabolism regulates cell state during homeostasis, tissue repair and disease has uncovered key roles for energy flux inside and outside of mitochondria. Fibroblasts are key mediators of wound healing outcomes and prior work uncovered that cells from highly regenerative mammals (spiny mice and rabbits) exhibit enhanced resistance to oxidative stress compared to those from non-regenerating laboratory mice and rats. Using a battery of cellular tests in primary ear pinna fibroblasts from spiny mice, rabbits, laboratory mice and rats, we show that cells from spiny mice and rabbits exhibit a baseline preference for glycolysis supporting lower ROS-production. Mitochondria from spiny mouse fibroblasts were generally low respiring and depolarized while exhibiting a large, spherical morphology. We observed this large, spherical phenotype consistently across lifespan in ear pinna fibroblasts from fetal, young and old spiny mice and cells from all ages were highly resistant to oxidative stress. While rabbit, mouse and rat fibroblasts had polarized tubular mitochondrial networks typical of adult mammalian fibroblasts, isolated rabbit and spiny mice fibroblasts shared lower oxygen consumption efficiency even in the absence of a potential gradient. Taken together, our results support that a shared metabolic signature exists in stromal cells from highly regenerative mammals, although possibly driven by different mechanisms, to converge on a ROS-resistant phenotype that increases cellular resilience.