PMID- 37337400 OWN - NLM STAT- MEDLINE DCOM- 20240221 LR - 20240221 IS - 1600-0781 (Electronic) IS - 0905-4383 (Linking) VI - 39 IP - 6 DP - 2023 Nov TI - A decrease of mitochondrial ubiquitin ligase increases the secretion of matrix metalloproteinase-1 by dermal fibroblasts through the induction of ER stress. PG - 582-588 LID - 10.1111/phpp.12897 [doi] AB - BACKGROUND: We previously reported that the level of mitochondrial ubiquitin ligase (MITOL) protein in fibroblasts was decreased by UVA and that the knock-down (KD) of MITOL increased the secretion of matrix metalloprotease-1 (MMP-1) by fibroblasts. A recent study reported that MITOL suppresses endoplasmic reticulum (ER) stress by stabilizing the interaction between ER and mitochondria (MT) through the ubiquitination of mitofusin 2. These facts suggest that a decrease of MITOL would increase the secretion of MMP-1 through ER stress, but the detailed mechanism of that process in dermal fibroblasts remains unclear. Thus, this study was conducted to clarify the involvement of ER stress in the oversecretion of MMP-1 induced by the decreased MT quality caused by MITOL-KD. METHODS: MITOL-KD normal human dermal fibroblast (NHDFs) were prepared by treating them with MITOL-small interfering RNA, after which their MMP-1 protein levels were measured. ER stress in NHDFs was evaluated by measuring the mRNA levels of spliced X-box binding protein 1 (sXBP1) and the protein levels of inositol-requiring enzyme 1alpha (IRE1alpha). RESULTS: MITOL-KD NHDFs enhanced the secretion of MMP-1 via interleukin-6 (IL-6) elicited by the activation of nuclear factor-kappa B (NF-kappaB). The secretion of MMP-1 could be abrogated by a neutralizing IL-6 antibody and by JSH23, which is an inhibitor of NF-kappaB activation. Furthermore, MITOL-KD NHDFs as well as UVA-irradiated NHDFs showed increased ER stress levels. In addition, tunicamycin, which is an inducer of ER stress, also increased MMP-1 secretion. CONCLUSION: These results suggested that the decrease of MITOL caused the oversecretion of MMP-1 via NF-kappaB-IL-6 signaling through the activation of ER stress in fibroblasts. CI - (c) 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. FAU - Katsuyama, Yushi AU - Katsuyama Y AUID- ORCID: 0000-0002-7608-3370 AD - CIEL CO., LTD, Sagamihara, Japan. FAU - Okano, Yuri AU - Okano Y AD - CIEL CO., LTD, Sagamihara, Japan. FAU - Masaki, Hitoshi AU - Masaki H AD - CIEL CO., LTD, Sagamihara, Japan. AD - Research Institute for Human Health Science, Konan University, Kobe, Japan. LA - eng PT - Journal Article DEP - 20230619 PL - England TA - Photodermatol Photoimmunol Photomed JT - Photodermatology, photoimmunology & photomedicine JID - 9013641 RN - EC 3.1.- (Endoribonucleases) RN - 0 (Interleukin-6) RN - EC 6.- (Ligases) RN - EC 3.4.24.7 (Matrix Metalloproteinase 1) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - 0 (NF-kappa B) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - 0 (Ubiquitins) RN - EC 2.3.2.27 (MARCHF5 protein, human) RN - EC 3.4.24.7 (MMP1 protein, human) SB - IM MH - Humans MH - Endoribonucleases/metabolism MH - Fibroblasts/metabolism MH - Interleukin-6 MH - Ligases/metabolism MH - *Matrix Metalloproteinase 1/genetics MH - Matrix Metalloproteinase 3/metabolism MH - *NF-kappa B/metabolism MH - Protein Serine-Threonine Kinases/genetics/metabolism MH - Ubiquitins/metabolism OTO - NOTNLM OT - endoplasmic reticulum stress OT - matrix metalloproteinase-1 OT - mitochondria OT - mitochondrial ubiquitin ligase EDAT- 2023/06/20 06:42 MHDA- 2024/02/12 18:42 CRDT- 2023/06/20 01:02 PHST- 2023/06/01 00:00 [revised] PHST- 2023/02/25 00:00 [received] PHST- 2023/06/07 00:00 [accepted] PHST- 2024/02/12 18:42 [medline] PHST- 2023/06/20 06:42 [pubmed] PHST- 2023/06/20 01:02 [entrez] AID - 10.1111/phpp.12897 [doi] PST - ppublish SO - Photodermatol Photoimmunol Photomed. 2023 Nov;39(6):582-588. doi: 10.1111/phpp.12897. Epub 2023 Jun 19.