Leal Ermelindo C, Emanuelli Tatiana, Santos Diana, Moura João, Catarina Rg Fonseca Ana, Burgeiro Ana, Carvalho Eugenia
Center for Neuroscience and Cell Biology, Center for Inovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.
Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
J Mol Endocrinol. 2023 Mar 8;70(3). doi: 10.1530/JME-22-0122. Print 2023 Apr 1.
Dysfunction in key cellular organelles has been linked to diabetic complications. This study intended to investigate the alterations in the unfolded protein response (UPR), autophagy, and mitochondrial function, which are part of the endoplasmic reticulum (ER) stress response, in wound healing (WH) under diabetes conditions. WH mouse models were used to evaluate the UPR, autophagy, mitochondrial fusion, fission, and biogenesis as well as mitophagy in the skin of control and diabetic mice at baseline and 10 days after wounding. The autophagic flux in response to high-glucose conditions was also evaluated in keratinocyte and fibroblast cell cultures. WH was impaired in the diabetic mouse model, and we found that the UPR and autophagy pathways were activated in skin wounds of control mice and in the non-wounded skin of diabetic mice. Moreover, high-glucose conditions induced autophagy in the keratinocyte and fibroblast cell cultures. However, mitophagy did not change in the skin of diabetic mice or the wounded skin. In addition, mitochondrial fusion was activated in control but not in the skin wounds of diabetic mice, while mitochondrial biogenesis is downregulated in the skin of diabetic mice. In conclusion, the activation of the UPR, autophagy, and mitochondrial remodeling are crucial for a proper WH. These results suggest that the increase in ER stress and autophagy in the skin of diabetic mice at baseline significantly escalated to pathological levels after wounding, contributing to impaired WH in diabetes.
关键细胞器功能障碍与糖尿病并发症有关。本研究旨在调查糖尿病条件下伤口愈合（WH）过程中未折叠蛋白反应（UPR）、自噬和线粒体功能的变化，这些都是内质网（ER）应激反应的一部分。使用WH小鼠模型评估对照小鼠和糖尿病小鼠在基线和受伤后10天皮肤中的UPR、自噬、线粒体融合、裂变和生物发生以及线粒体自噬。还在角质形成细胞和成纤维细胞培养物中评估了对高糖条件的自噬通量。糖尿病小鼠模型中的WH受损，我们发现UPR和自噬途径在对照小鼠的皮肤伤口和糖尿病小鼠的未受伤皮肤中被激活。此外，高糖条件在角质形成细胞和成纤维细胞培养物中诱导自噬。然而，糖尿病小鼠皮肤或受伤皮肤中的线粒体自噬没有变化。此外，对照小鼠皮肤中的线粒体融合被激活，而糖尿病小鼠皮肤伤口中的线粒体融合未被激活，同时糖尿病小鼠皮肤中的线粒体生物发生下调。总之，UPR、自噬和线粒体重塑的激活对于适当的WH至关重要。这些结果表明，糖尿病小鼠基线时皮肤中ER应激和自噬的增加在受伤后显著升级到病理水平，导致糖尿病中WH受损。
