Cyclobutane pyrimidine dimers from UVB exposure induce a hypermetabolic state in keratinocytes via mitochondrial oxidative stress
Csaba Hegedűs,
Tamás Juhász,
Eszter Fidrus,
Eszter Anna Janka,
Gábor Juhász,
Gábor Boros,
György Paragh,
Karen Uray,
Gabriella Emri,
Éva Remenyik,
Péter Bai
Affiliations
Csaba Hegedűs
Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary; University of Debrecen, Doctoral School of Health Sciences, 4032, Debrecen, Hungary
Tamás Juhász
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
Eszter Fidrus
Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary; University of Debrecen, Doctoral School of Health Sciences, 4032, Debrecen, Hungary
Eszter Anna Janka
Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
Gábor Juhász
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 Dermatology and Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, 665 Elm St, Buffalo, NY, 14203, USA
Karen Uray
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
Gabriella Emri
Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
Éva Remenyik
Department of Dermatology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary; Corresponding author.
Péter Bai
Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism Research Group, University of Debrecen, 4032, Debrecen, Hungary; Research Center for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary; Corresponding author. University of Debrecen, Department of Medical Chemistry, 4032, Debrecen, Egyetem tér 1., Hungary.
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.
