Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance

Algieri et al. Journal of Translational Medicine https://doi.org/10.1186/s12967-025-07392-4 Journal of Translational Medicine (2025) 23:1321 Open Access REVIEW Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance Cristina Algieri1*, Salvatore Nesci1* and Francesca Oppedisano2* Abstract Mitochondria, in addition to their classic role in energy production, have emerged as central hubs in the regulation of innate immunity. Under conditions of cellular stress, mitochondrial dysfunction triggers the release of mitochondrial DNA (mtDNA) into the cytosol or extracellular space, activating potent inflammatory pathways such as cGAS-STING, NLRP3 and TLR9. mtDNA release, driven by factors such as oxidative damage, membrane permeabilization, and various cell death pathways, is involved in immune surveillance and the pathogenesis of various diseases. At the same time, this downstream event leads to profound reorganization of immune cell metabolism, influencing functional polarization and inflammatory outcomes. This review presents the mitochondrion as an interface between metabolism, immunity, immunometabolites, and danger signalling. We explore the molecular mechanisms of mtDNA release, its conversion into immune signals, and its impact on metabolism in immune cells. Translational implications for pathologies such as neurodegenerative, autoimmune, and neoplastic diseases are also discussed. Deciphering the interconnection between mitochondrial stress, mtDNA release, and immunometabolic rewiring could open new avenues for the treatment of complex diseases and drive innovation in immunotherapy and regenerative medicine. Keywords Mitochondria, Immunity, Inflammation, Metabolism, Complex diseases *Correspondence: Cristina Algieri Salvatore Nesci Francesca Oppedisano 1 Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, Bologna, BO, Italy 2 Department of Health Sciences, Institute of Research for Food Safety and Health (IRC-FSH), University “Magna Græcia” of Catanzaro, Catanzaro, CZ, Italy Introduction Mitochondria are not only central to cellular energy metabolism (oxidative phosphorylation (OXPHOS) and ATP production) but also serve as key regulators of innate immunity by modulating inflammatory signalling and acting as a major source of damage-associated molecular patterns (DAMPs), including mitochondrial DNA (mtDNA) and reactive oxygen species (ROS) [1]. Under cellular stress, mitochondrial integrity is compromised, leading to the release of mtDNA into the cytosol. Owing to its structural differences from nuclear DNA, mtDNA functions as a potent DAMP [2], establishing a molecular link between mitochondrial © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Algieri et al. Journal of Translational Medicine (2025) 23:1321 dysfunction, immunometabolic reprogramming, and innate immune activation. Understanding these interconnected processes is essential for elucidating how mitochondrial stress drives sterile inflammation and contributes to chronic disease pathogenesis [3]. The relationship between mitochondrial health and immune function is particularly evident in macrophages, key effectors of innate immunity. These cells exhibit remarkable plasticity, polarizing into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes in response to environmental cues [4]. This functional diversity is closely tied to metabolic programming. Mitochondrial dysfunction disrupts this balance, driving metabolic rewiring, accumulation of inflammatory intermediates such as succinate, and increased ROS production. Importantly, impaired mitochondrial integrity and mtDNA release amplify innate immune signalling and influence macrophage polarization. Herein, we investigate the intricate interplay between mitochondrial dysfunction, DAMP signalling, and immunometabolic reprogramming that underlies the pathogenesis of numerous disorders. Evidence indicates that mitochondrial impairment in immune cells, particularly macrophages, exacerbates inflammation in diverse conditions, including cardiovascular injury [5], ischemiareperfusion damage [6], infectious diseases [7], immunodeficiency diseases [3] and cancer [2, 8]. Deciphering how mitochondrial dysfunction governs macrophage metabolism and polarization is therefore critical for understanding innate immunosurveillance and developing novel therapeutic strategies for chronic inflammatory and immune-mediated diseases. Role of metabolism in cell polarization of innate immune response As the most important innate immune cells and effective antigen-presenting cells, macrophages are remarkably versatile. By identifying risk factors, they initiate the natural immune response; conversely, they modify host immunity by polarizing into different phenotypes in response to microenvironmental changes. Furthermore, the host’s immunological homeostasis depends on the delicate balance of macrophages in various polarization states, each of which performs a variety of activities [9]. In order to reduce inflammatory disorders, it is therefore of great importance to modify macrophage activation by encouraging the repolarization of M1 macrophages to M2 macrophages [10]. In order to assure effective microbial death, M1 macrophages generate reactive oxygen and nitrogen species, secrete pro-inflammatory cytokines, and exhibit increased expression of MHC-I/II, CD80, and CD86. On the other hand, persistent M1 activation might result in chronic inflammation and collateral tissue damage. Additionally, a variety of non-inflammatory Page 2 of 12 stimuli can activate macrophages. In terms of function, M2 macrophages mediate Th2cytokines-driven diseases, encourage tissue repair, and reduce Th1/M1-driven inflammation. M2 macrophages are distinguished at the molecular level by a variety of distinct marker genes, surface markers, and enzymes [11]. A novel therap (...truncated)