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  2. Increased mitochondrial fission induces NLRP3/cGAS-STING mediated pro-inflammatory pathways and apoptosis in UVB-irradiated immortalized human keratinocyte HaCaT cells

Increased mitochondrial fission induces NLRP3/cGAS-STING mediated pro-inflammatory pathways and apoptosis in UVB-irradiated immortalized human keratinocyte HaCaT cells

  • Arch Biochem Biophys. 2023 Mar 4;109558. doi: 10.1016/j.abb.2023.109558.
Can Li 1 Yuying Zhu 1 Weiwei Liu 1 Toshihiko Hayashi 2 Wendie Xiang 1 Sijun He 1 Kazunori Mizuno 3 Shunji Hattori 3 Hitomi Fujisaki 3 Takashi Ikejima 4
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China.
  • 2 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China; Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan.
  • 3 Nippi Research Institute of Biomatrix, Toride, Ibaraki, 302-0017, Japan.
  • 4 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, PR China; Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning, PR China. Electronic address: ikejimat@vip.sina.com.
Abstract

Ultraviolet B (UVB) irradiation causes skin inflammation and Apoptosis. Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in skin damages, little is known about the roles of mitochondrial dynamics in these processes. UVB irradiation increases abnormal mitochondrial content but decreases mitochondrial volume in immortalized human keratinocyte HaCaT cells. UVB irradiation resulted in marked upregulation of mitochondrial fission protein dynamin-related protein 1 (DRP1) and downregulation of mitochondrial outer membrane fusion proteins 1 and 2 (MFN1 and MFN2) in HaCaT cells. Mitochondrial dynamics was discovered to be crucial for NLRP3 inflammasome and cGAS-STING pathway activation, as well as the induction of Apoptosis. Inhibition of mitochondrial fission by treatments with a DRP1 inhibitor, mdivi-1, or with DRP1-targeted siRNA, efficiently prevented UVB-induced NLRP3/cGAS-STING mediated pro-inflammatory pathways or Apoptosis in the HaCaT cells, whereas inhibition of mitochondrial fusion with MFN1and 2 siRNA increased these pro-inflammatory pathways or Apoptosis. The enhanced mitochondrial fission and reduced fusion caused the up-regulation of Reactive Oxygen Species (ROS). Application of an antioxidant, N-acetyl-l-cysteine (NAC), which scavenges excessive ROS, attenuated inflammatory responses through suppressing NLRP3 inflammasome and cGAS-STING pathway activation, and rescued cells from Apoptosis caused by UVB-irradiation. Together, our findings revealed the regulation of NLRP3/cGAS-STING inflammatory pathways and Apoptosis by mitochondrial fission/fusion dynamics in UVB-irradiated HaCaT cells, providing a new strategy for the therapy of UVB skin injury.

Keywords

Apoptosis; DRP1; Inflammation; MFN1 and MFN2; Mitochondrial fission; ROS; UVB.

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