Loss of O<sup>6</sup>-methylguanine DNA methyltransferase (MGMT) in macrophages alters responses to TLR3 stimulation and enhances DNA double-strand breaks and mitophagy
Issued Date
2024-11-11
Resource Type
eISSN
20452322
Scopus ID
2-s2.0-85209479777
Pubmed ID
39528715
Journal Title
Scientific reports
Volume
14
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Scientific reports Vol.14 No.1 (2024) , 27492
Suggested Citation
Haque M.F., Benjaskulluecha S., Boonmee A., Kongkavitoon P., Wongprom B., Pattarakankul T., Ongratanaphol R., Sri-Ngern-Ngam K., Pongma C., Saechue B., Kueanjinda P., Kobayashi T., Leelahavanichkul A., Palaga T. Loss of O<sup>6</sup>-methylguanine DNA methyltransferase (MGMT) in macrophages alters responses to TLR3 stimulation and enhances DNA double-strand breaks and mitophagy. Scientific reports Vol.14 No.1 (2024) , 27492. doi:10.1038/s41598-024-78885-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/102163
Title
Loss of O<sup>6</sup>-methylguanine DNA methyltransferase (MGMT) in macrophages alters responses to TLR3 stimulation and enhances DNA double-strand breaks and mitophagy
Corresponding Author(s)
Other Contributor(s)
Abstract
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA damage repair enzyme. The roles of this enzyme in immune cells remain unclear. In this study, we explored the roles of MGMT in bone marrow-derived murine macrophages (BMMs) via the use of MGMT knockout (KO) mice. Loss of MGMT altered the response to TLR3 agonists (poly (I:C)), such as dampening the production of TNFα and IL-6. Increased DNA double-strand breaks (DSBs) were observed in MGMT-KO macrophages but did not result in increased cell death. MGMT localized to both nuclei and mitochondria at increasing levels during poly (I:C) stimulation. MGMT deficiency increased the production of mitochondrial reactive oxygen species (mtROS), which was correlated with increased mitophagy. The underlying mechanism involves mediation through activation of the AMPKα pathway. Taken together, our findings reveal the roles of MGMT in macrophages in regulating the response to TLR3, which links DSBs to mtROS and mitophagy via the AMPKα pathway. These roles may have consequences for the inflammatory response and chronic inflammation.