2025-11-19 カリフォルニア大学リバーサイド校 (UCR)
<関連情報>
- https://news.ucr.edu/articles/2025/11/19/new-type-dna-damage-found-our-cells-powerhouses
- https://www.pnas.org/doi/full/10.1073/pnas.2509312122
グルタチオン化DNA付加物はミトコンドリアDNAに蓄積し、APエンドヌクレアーゼ1とチロシルDNAホスホジエステラーゼ1によって制御される Glutathionylated DNA adducts accumulate in mitochondrial DNA and are regulated by AP endonuclease 1 and tyrosyl-DNA phosphodiesterase 1
Yu Hsuan Chen, Martin Esparza Sanchez, Ta I Hung, +7 , and Linlin Zhao
Proceedings of the National Academy of Sciences Published:November 19, 2025
DOI:https://doi.org/10.1073/pnas.2509312122
Significance
Mitochondrial DNA (mtDNA) plays a crucial role in energy metabolism, cellular signaling, and human disease development. While it is known that mtDNA is susceptible to damage, the biological consequences of this damage remain partially understood. We report a type of mtDNA damage, glutathionylated DNA (GSH-DNA) adducts. These adducts form from endogenous abasic sites and alkylation DNA damage, catalyzed by a mtDNA packing protein (TFAM) and polyamines. Our study clarifies their accumulation, regulation, and biological effects in mitochondria. Given the emerging role of mtDNA and a commonly used oxidative DNA damage marker, 8-oxo-7,8-dihydro-2’-deoxyguanosine, in promoting inflammation, the high levels of GSH-DNA adducts in mtDNA highlight the critical need to investigate their roles in innate immune and inflammatory diseases.
Abstract
Mitochondrial DNA (mtDNA) is crucial for cellular energy production, metabolism, and signaling. Its dysfunction is implicated in various diseases, including mitochondrial disorders, neurodegeneration, and diabetes. mtDNA is susceptible to damage by endogenous and environmental factors; however, unlike nuclear DNA (nDNA), mtDNA lesions do not necessarily lead to an increased mutation load in mtDNA. Instead, mtDNA lesions have been implicated in innate immunity and inflammation. Here, we report a type of mtDNA damage: glutathionylated DNA (GSH-DNA) adducts. These adducts are formed from abasic (AP) sites, key intermediates in base excision repair, or from alkylation DNA damage. Using mass spectrometry, we quantified the GSH-DNA lesion in both nDNA and mtDNA and found its significant accumulation in mtDNA of two different human cell lines, with levels one or two orders of magnitude higher than in nDNA. The formation of GSH-DNA adducts is influenced by TFAM and polyamines, and their levels are regulated by repair enzymes AP endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1). The accumulation of GSH-DNA adducts is associated with the downregulation of several ribosomal and complex I subunit proteins and the upregulation of proteins related to redox balance and mitochondrial dynamics. Molecular dynamics (MD) simulations revealed that the GSH-DNA lesion stabilizes the TFAM-DNA binding, suggesting shielding effects from mtDNA transactions. Collectively, this study provides critical insights into the formation, regulation, and biological effects of GSH-DNA adducts in mtDNA. Our findings underscore the importance of understanding how these lesions may contribute to innate immunity and inflammation.
