ArticleCell death & disease2023
Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cells.
Article in Cell death & disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 8 citations in OpenAlex.
- Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.Cell communication and signaling : CCS · 2026Review
- CX3CL1 deficiency ameliorates acute kidney injury by inhibiting macrophage mitochondrial dysfunction and mtDNA-cGAS-STING signaling.Cell death discovery · 2025Article
- The STING signaling pathways and bacterial infection.Apoptosis : an international journal on programmed cell death · 2025Review
- BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.Journal of experimental & clinical cancer research : CR · 2024Article
- DNA-PKcs Phosphorylates Cofilin2 to Induce Endothelial Dysfunction and Microcirculatory Disorder in Endotoxemic Cardiomyopathy.Research (Washington, D.C.) · 2024Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
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 β1 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 І 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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