Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cellsopen access
- Authors
- Heo, June; Park, Yeon-Ji; Kim, Yonghyeon; Lee, Ho-Soo; Kim, Jeongah; Kwon, Soon-Hwan; Kang, Myeong-Gyun; Rhee, Hyun-Woo; Sun, Woong; Lee, Jae-Ho; Cho, Hyeseong
- Issue Date
- Dec-2023
- Publisher
- SPRINGERNATURE
- Citation
- Cell Death and Disease, v.14, no.12
- Indexed
- SCIE
SCOPUS
- Journal Title
- Cell Death and Disease
- Volume
- 14
- Number
- 12
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/64970
- DOI
- 10.1038/s41419-023-06315-9
- ISSN
- 2041-4889
- Abstract
- Mitochondrial dysfunction is important in various chronic degenerative disorders, and aberrant immune responses elicited by cytoplasmic mitochondrial DNA (mtDNA) may be related. Here, we developed mtDNA-targeted MTERF1-FokI and TFAM-FokI endonuclease systems to induce mitochondrial DNA double-strand breaks (mtDSBs). In these cells, the mtDNA copy number was significantly reduced upon mtDSB induction. Interestingly, in cGAS knockout cells, synthesis of interferon beta 1 and interferon-stimulated gene was increased upon mtDSB induction. We found that mtDSBs activated DNA-PKcs and HSPA8 in a VDAC1-dependent manner. Importantly, the mitochondrial E3 ligase MARCH5 bound active DNA-PKcs in cells with mtDSBs and reduced the type CYRILLIC CAPITAL LETTER BYELORUSSIAN-UKRAINIAN I interferon response through the degradation of DNA-PKcs. Likewise, mitochondrial damage caused by LPS treatment in RAW264.7 macrophage cells increased phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA in a DNA-PKcs-dependent manner. Accordingly, in March5 knockout macrophages, phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA were prolonged after LPS stimulation. Together, cytoplasmic mtDNA elicits a cellular immune response through DNA-PKcs, and mitochondrial MARCH5 may be a safeguard to prevent persistent inflammatory reactions.
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- Appears in
Collections - 1. Basic Science > Department of Anatomy > 1. Journal Articles
- 3. Graduate School > Graduate School > 1. Journal Articles
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