Cyclobutane pyrimidine dimers from UVB exposure induce a hypermetabolic state in keratinocytes via mitochondrial oxidative stress

Redox Biology

Gábor Juhász¹  Tamás Juhász¹  Karen Uray²  György Paragh³  Eszter Fidrus⁴  Gabriella Emri⁵  Gábor Boros⁶  Péter Bai⁶  Eszter Anna Janka⁶  Csaba Hegedűs⁶  Éva Remenyik⁷ 

[1] University of Debrecen, Doctoral School of Health Sciences, 4032, Debrecen, Hungary;BioNTech RNA Pharmaceuticals GmbH, BioNTech AG, 55131, Mainz, Germany;Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, 1117 Budapest, Hungary and Institute of Genetics, Biological Research Centre, 6726, Szeged, Hungary;Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary;Department of Dermatology and Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY, 14203, USA;Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary;Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary;

关键词: UVB;    CPD;    Photolyase mRNA;    Mitochondria;    Keratinocyte;   

DOI  :  

来源: DOAJ

【 摘 要 】

Ultraviolet B radiation (UVB) is an environmental complete carcinogen, which induces and promotes keratinocyte carcinomas, the most common human malignancies. UVB induces the formation of cyclobutane pyrimidine dimers (CPDs). Repairing CPDs through nucleotide excision repair is slow and error-prone in placental mammals. In addition to the mutagenic and malignancy-inducing effects, UVB also elicits poorly understood complex metabolic changes in keratinocytes, possibly through CPDs. To determine the effects of CPDs, CPD-photolyase was overexpressed in keratinocytes using an N1-methyl pseudouridine-containing in vitro-transcribed mRNA. CPD-photolyase, which is normally not present in placental mammals, can efficiently and rapidly repair CPDs to block signaling pathways elicited by CPDs. Keratinocytes surviving UVB irradiation turn hypermetabolic. We show that CPD-evoked mitochondrial reactive oxygen species production, followed by the activation of several energy sensor enzymes, including sirtuins, AMPK, mTORC1, mTORC2, p53, and ATM, is responsible for the compensatory metabolic adaptations in keratinocytes surviving UVB irradiation. Compensatory metabolic changes consist of enhanced glycolytic flux, Szent-Györgyi-Krebs cycle, and terminal oxidation. Furthermore, mitochondrial fusion, mitochondrial biogenesis, and lipophagy characterize compensatory hypermetabolism in UVB-exposed keratinocytes. These properties not only support the survival of keratinocytes, but also contribute to UVB-induced differentiation of keratinocytes. Our results indicate that CPD-dependent signaling acutely maintains skin integrity by supporting cellular energy metabolism.

【 授权许可】

Unknown