The role of fibroblast growth factor 21 in different mouse models of mitochondrial dysfunction

Mitochondrial dysfunction is the cause of many diseases that vary in their complexity and clinical presentation. Flawed mitochondrial protein synthesis can disrupt the homeostasis of the whole cell and activate different stress responses, which are trying to outweigh the damage. Both the depletion of mitochondrial aspartyl-tRNA synthethase (Dars2) in a tissue-specific manner and ATP-dependent Clp protease (Clpp) in whole body, leads to the activation of versatile stress responses. Remarkably, in both mouse models, we observed a significant increase in the expression of a mitokine fibroblast growth factor 21 (Fgf21). This mitokine was shown to be upregulated in many different mouse models with mitochondrial dysfunction, however, its role has still not been clearly demonstrated. In this study, we generated different double-deficient mouse models, in order to access the role of FGF21 in mitochondrial dysfunction. The results have shown that the autocrine role of FGF21 in DARS2-deficient cardiomyocytes is dispensable and the non-cell autonomous effects of the topical DARS2 depletion are independent of FGF21. Furthermore, with the depletion of FGF21 in whole body, we have shown that DARS2-deficient animals are not affected, indicating that alternative signaling pathways might be activated. Remarkably, when FGF21 was depleted in CLPP deficient animals, we observed an increase in the markers of cardiomyopathy suggesting importance of this mitokine in cardiac physiology. In summary, these results have shown that FGF21 is not a key player mediating stress responses upon strong mitochondrial deficiency, as modeled in DARS2-deficient mice. However, this cytokine might have a more significant role in late-onset mitochondrial diseases that are modeled by the CLPP loss, which is featured by mild mitochondrial dysfunction. Moreover, the observed expression of Fgf21 might be dose-dependent and therefore mirroring the severity of mitochondrial dysfunction. In addition, there are possibly alternative players compensating for the lack of FGF21 in mouse models with mitochondrial disease