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A decrease of mitochondrial ubiquitin ligase increases the secretion of matrix metalloproteinase-1 by dermal
Yushi Katsuyama1, Yuri Okano1, Hitoshi Masaki1,2
1CIEL CO., LTD, Sagamihara, Japan.
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 1α (IRE1α).
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-κB). The secretion of MMP-1 could be abrogated by a neutralizing IL-6 antibody and by JSH23, which is an inhibitor of NF-κB 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-κB-IL-6 signaling through the activation of ER stress in fibroblasts.
Insights
Decreased mitochondrial ubiquitin ligase (MITOL) activates endoplasmic reticulum (ER) stress, leading to increased matrix metalloprotease-1 (MMP-1) secretion in fibroblasts via NF-κB and IL-6 signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Dermatology
Background:
- Mitochondrial ubiquitin ligase (MITOL) protein levels decrease with UVA exposure.
- Knock-down (KD) of MITOL increases fibroblast secretion of matrix metalloprotease-1 (MMP-1).
- MITOL is known to suppress endoplasmic reticulum (ER) stress.
Purpose of the Study:
- To investigate the mechanism by which decreased MITOL leads to MMP-1 oversecretion.
- To clarify the role of ER stress in MITOL-KD-induced MMP-1 secretion in dermal fibroblasts.
Main Methods:
- Prepared MITOL-knockdown normal human dermal fibroblasts (NHDFs).
- Measured MMP-1 protein levels in NHDFs.
- Assessed ER stress by quantifying spliced X-box binding protein 1 (sXBP1) mRNA and inositol-requiring enzyme 1α (IRE1α) protein levels.
Main Results:
- MITOL-KD NHDFs showed enhanced MMP-1 secretion mediated by interleukin-6 (IL-6) and nuclear factor-kappa B (NF-κB) activation.
- MMP-1 secretion was reduced by IL-6 neutralizing antibodies and an NF-κB inhibitor (JSH23).
- Both MITOL-KD and UVA-irradiated NHDFs exhibited increased ER stress; tunicamycin also elevated MMP-1 secretion.
Conclusions:
- A decrease in MITOL induces MMP-1 oversecretion.
- This process involves the activation of ER stress, leading to NF-κB and IL-6 signaling pathways.
- ER stress plays a crucial role in the relationship between MITOL levels and MMP-1 secretion in fibroblasts.
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