{"id":3546,"date":"2026-08-31T01:50:20","date_gmt":"2026-08-31T01:50:20","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/medphc\/?p=3546"},"modified":"2026-08-31T01:50:20","modified_gmt":"2026-08-31T01:50:20","slug":"from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases","status":"publish","type":"post","link":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\/","title":{"rendered":"From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases"},"content":{"rendered":"<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone  wp-image-3547\" src=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/08\/20260304-GS-300x169.jpg\" alt=\"\" width=\"850\" height=\"479\" srcset=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/08\/20260304-GS-300x169.jpg 300w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/08\/20260304-GS-1024x576.jpg 1024w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/08\/20260304-GS-768x432.jpg 768w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/08\/20260304-GS.jpg 1280w\" sizes=\"auto, (max-width: 850px) 100vw, 850px\" \/><\/p>\n<h2 id=\"Abs1\" class=\"c-article-section__title js-section-title js-c-reading-companion-sections-item\">Abstract<\/h2>\n<div id=\"Abs1-content\" class=\"c-article-section__content\">\n<p>Mitochondria, descendants of ancestral \u03b1-proteobacteria, embody a dual identity that unites metabolic symbiosis with immune regulation. While evolution has transformed their form and function, mitochondria still preserve a tripartite heritage, an outer membrane resembling the host, an inner membrane of bacterial origin, and a matrix enriched with prokaryotic remnants such as unmethylated mitochondrial DNA (mtDNA), N-formyl peptides, and cardiolipin. Under physiological conditions, this architecture supports efficient energy generation while maintaining immunological silence. However, during infection, hypoxia, or systemic inflammation, this endosymbiotic equilibrium collapses, reawakening innate immune programs encoded in their bacterial ancestry. This review introduces the framework of Mitochondrial Endosymbiotic Dysregulation (MED) to describe the progressive transition of mitochondria from metabolic collaborators to immune activators under inflammatory stress. The MED model delineates three sequential stages: MED-I (Adaptive Remodeling), where mitochondria dynamically reorganize to preserve homeostasis, exhibiting characteristic structures such as mitochondrial flagella-like acquisition and retrieval extension (mitoFLARE) and mito-donut; MED-II (Functional Collapse), characterized by the failure of mitochondrial communication and the emergence of defensive structures such as mito-matryoshka; and MED-III (Structural Disintegration), marked by membrane rupture, release of mitochondrial damage-associated molecular patterns (DAMPs), and amplification of innate immune cascades. Rather than viewing mitochondrial dysfunction as a passive byproduct of injury, the MED paradigm reframes it as a reactivation of ancient bacterial defense programs, coupling bioenergetic failure to immune amplification. Thus, by integrating evolutionary, structural, and immunometabolic perspectives, this review discusses how mitochondrial remodeling under inflammatory stress contributes to diseases such as sepsis, autoimmune disorders, and neuroinflammation, and explores emerging therapeutic strategies aimed at restoring mitochondrial\u2013host symbiosis.<\/p>\n<p>Full Article:\u00a0<a href=\"https:\/\/link.springer.com\/article\/10.1186\/s12964-026-02736-z\">https:\/\/link.springer.com\/article\/10.1186\/s12964-026-02736-z<\/a><\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Abstract Mitochondria, descendants of ancestral \u03b1-proteobacteria, embody a dual identity that unites metabolic symbiosis with immune regulation. While evolution has transformed their form and function, mitochondria still preserve a tripartite heritage, an outer membrane resembling the host, an inner membrane of bacterial origin, and a matrix enriched with prokaryotic remnants such as unmethylated mitochondrial DNA [&hellip;]<\/p>\n","protected":false},"author":9345,"featured_media":3547,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"default","adv-header-id-meta":"","stick-header-meta":"default","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"set","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[5],"tags":[],"class_list":["post-3546","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.0 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases - Pharmacology<\/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:\/\/medicine.nus.edu.sg\/medphc\/publications\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases - Pharmacology\" \/>\n<meta property=\"og:description\" content=\"Abstract Mitochondria, descendants of ancestral \u03b1-proteobacteria, embody a dual identity that unites metabolic symbiosis with immune regulation. While evolution has transformed their form and function, mitochondria still preserve a tripartite heritage, an outer membrane resembling the host, an inner membrane of bacterial origin, and a matrix enriched with prokaryotic remnants such as unmethylated mitochondrial DNA [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\/\" \/>\n<meta property=\"og:site_name\" content=\"Pharmacology\" \/>\n<meta property=\"article:published_time\" content=\"2026-08-31T01:50:20+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2026\/08\/20260304-GS.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1280\" \/>\n\t<meta property=\"og:image:height\" content=\"720\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Woon Fei\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Woon Fei\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\\\/\"},\"author\":{\"name\":\"Woon Fei\",\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/#\\\/schema\\\/person\\\/ea3ccd10ab2f2bba51fd804396287cb0\"},\"headline\":\"From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases\",\"datePublished\":\"2026-08-31T01:50:20+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\\\/\"},\"wordCount\":283,\"publisher\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/#organization\"},\"image\":{\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\\\/#primaryimage\"},\"thumbnailUrl\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/wp-content\\\/uploads\\\/sites\\\/33\\\/2026\\\/08\\\/20260304-GS.jpg\",\"articleSection\":[\"Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\\\/\",\"url\":\"https:\\\/\\\/medicine.nus.edu.sg\\\/medphc\\\/publications\\\/from-symbiosis-to-immunity-the-evolutionary-revival-of-mitochondrial-defense-programs-in-inflammatory-diseases\\\/\",\"name\":\"From symbiosis to immunity: the evolutionary revival of mitochondrial defense programs in inflammatory diseases - 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