Dysregulation of endoplasmic reticulum stress response in skin wounds in a streptozotocin-induced diabetes mouse model

in Journal of Molecular Endocrinology
Authors:
Ermelindo C LealCenter for Neuroscience and Cell Biology, Center for Inovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal

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Tatiana EmanuelliCenter 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

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Diana SantosCenter 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

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João MouraCenter for Neuroscience and Cell Biology, Center for Inovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal

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Ana Catarina RG FonsecaCenter for Neuroscience and Cell Biology, Center for Inovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal

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Ana BurgeiroCenter for Neuroscience and Cell Biology, Center for Inovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal

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Eugenia CarvalhoCenter 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
Associação Protectora dos Diabéticos de Portugal (APDP), Lisbon, Portugal

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Correspondence should be addressed to E C Leal or E Carvalho: ecleal@cnc.uc.pt or ecarvalh@cnc.uc.pt

*(E C Leal and T Emanuelli contributed equally to this work)

DOI:
https://doi.org/10.1530/JME-22-0122
Volume/Issue:
Volume 70: Issue 3
Article Type:
Research Article
Article ID:
e220122
Online Publication Date:
08 Mar 2023
Copyright:
© Society for Endocrinology 2023
Restricted access

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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.

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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© Society for Endocrinology 2023
Article ID:
e220122
Article Type:
Research Article
Received Date:
05 Dec 2022
Accepted Date:
02 Feb 2023
Print Publication Date:
01 Apr 2023
Online Publication Date:
08 Mar 2023
Keywords:
diabetes; wound healing; unfolded protein response; endoplasmic reticulum; autophagy; mitochondria

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