Variations in cellular unfolded protein response, respiratory capacity, and stress tolerance in skin and lung fibroblasts of deer mice (Peromyscus maniculatus)

Evolutionary physiologists have long been interested in physiological mechanisms underpinning variation in life-history performance. Recent efforts to elucidate these mechanisms focused on bioenergetics and oxidative stress. One underappreciated area that could play a role in mediating variation in performance is the unfolded protein response (UPR), a cellular stress response that reduces secretory protein load, enhances endoplasmic reticulum (ER) protein folding and clearance capacity during stress and during its adaptive phase. Given that the ER and mitochondria interact to regulate cellular homeostasis, it seems intuitive that UPR phenotype would correlate strongly with mitochondrial physiology, which in turn would contribute to variations in whole-organism metabolism. One way researchers have been studying cellular controls of life-history traits is by assessing stress resistance and bioenergetic properties of primary dermal fibroblasts. However, it is unclear if findings from dermal fibroblasts can be generalized to other cell and tissue types, and if fibroblasts phenotypes are repeatable across different life-history stages. This study aimed to explore the relationships between UPR profile, cellular respiration, and stress resistance using primary dermal fibroblasts isolated at puberty and primary lung fibroblasts isolated at adulthood. Specifically, we tested if 1) UPR profile of dermal fibroblasts isolated at puberty corresponds to UPR profile of lung fibroblasts isolated at adulthood, 2) UPR profile of dermal fibroblasts isolated at puberty and lung fibroblasts isolated at adulthood correspond to cellular bioenergetics of lung fibroblasts isolated at adulthood, and 3) UPR profile of dermal fibroblasts isolated at puberty corresponds to multiplex stress resistance (ER stress, oxidative stress, DNA damage) of lung fibroblasts isolated at adulthood. We found that only tunicamycin induced BiP expression was repeatable in skin and lung fibroblasts. Tunicamycin induced expressions of BiP, GRP94, and CNX in skin fibroblasts predicted resistance of lung fibroblasts to tunicamycin, (but not thapsigargin and other inducers of lethal stress), which is indicative for the pro-survival role of UPR during stress. Tunicamycin induced BiP expression in skin and lung fibroblasts also predicted multiple cellular bioenergetics parameters in lung fibroblasts. Statements and DeclarationsNo competing interests declared. This work was supported by National Science Foundation grants IOS1453784 and OIA1736150 to W.R.H., IOS1755670 to the PGSC, and a National Science Foundation EPSCoR pilot grant to K.N.Y. The funders did not have any input into the content of the manuscript nor require approval prior to submission.