{"id":107429,"date":"2024-03-25T20:30:47","date_gmt":"2024-03-26T00:30:47","guid":{"rendered":"https:\/\/med.virginia.edu\/cell-biology\/?p=107429"},"modified":"2026-07-09T12:56:21","modified_gmt":"2026-07-09T16:56:21","slug":"mitochondrial-dna-replication-stress-triggers-a-pro-inflammatory-endosomal-pathway-of-nucleoid-disposal","status":"publish","type":"post","link":"https:\/\/med.virginia.edu\/cell-biology\/2024\/03\/25\/mitochondrial-dna-replication-stress-triggers-a-pro-inflammatory-endosomal-pathway-of-nucleoid-disposal\/","title":{"rendered":"Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal"},"content":{"rendered":"<p><strong>UVA Author:<\/strong> Laura Newman<br \/>\n<strong>Citation:<\/strong> Newman LE, Weiser Novak S, Rojas GR, Tadepalle N, Schiavon CR, Grotjahn DA, Towers CG, Tremblay M\u00c8, Donnelly MP, Ghosh S, Medina M, Rocha S, Rodriguez-Enriquez R, Chevez JA, Lemersal I, Manor U, Shadel GS. Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal. Nat Cell Biol. 2024 Feb;26(2):194-206. doi: 10.1038\/s41556-023-01343-1. Epub 2024 Feb 8. PMID: 38332353.<\/p>\n<p><strong>DOI:<\/strong> <a>https:\/\/doi.org\/10.1038\/s41556-023-01343-1<\/a><br \/>\n<strong>Pub-Med Number<\/strong>: 38332353<\/p>\n<hr \/>\n<p>Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA\u2013protein complexes) and activation of cGAS\u2013STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS\u2013STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS\u2013STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria\u2013endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>UVA Author: Laura Newman Citation: Newman LE, Weiser Novak S, Rojas GR, Tadepalle N, Schiavon CR, Grotjahn DA, Towers CG, Tremblay M\u00c8, Donnelly MP, Ghosh S, Medina M, Rocha S, Rodriguez-Enriquez R, Chevez JA, Lemersal I, Manor U, Shadel GS. Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal. Nat Cell Biol. [&hellip;]<\/p>\n","protected":false},"author":1740,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"inline_featured_image":false,"footnotes":"","_members_access_role":[],"_members_access_error":"","_links_to":"","_links_to_target":""},"categories":[13],"tags":[23],"class_list":["post-107429","post","type-post","status-publish","format-standard","hentry","category-featured-publications","tag-department-news"],"acf":false,"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.1 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal - Department of Cell Biology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/med.virginia.edu\/cell-biology\/2024\/03\/25\/mitochondrial-dna-replication-stress-triggers-a-pro-inflammatory-endosomal-pathway-of-nucleoid-disposal\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal - Department of Cell Biology\" \/>\n<meta property=\"og:description\" content=\"UVA Author: Laura Newman Citation: Newman LE, Weiser Novak S, Rojas GR, Tadepalle N, Schiavon CR, Grotjahn DA, Towers CG, Tremblay M\u00c8, Donnelly MP, Ghosh S, Medina M, Rocha S, Rodriguez-Enriquez R, Chevez JA, Lemersal I, Manor U, Shadel GS. Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal. Nat Cell Biol. 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Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal. Nat Cell Biol. 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