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Mitochondrial DNA and Mitochondrial-Derived Vesicles as Immunometabolic Modulators of Innate Immunosurveillance through Control of the Mitochondrial Permeability Transition Pore

  • Salvatore Nesci 1,*,   
  • Patrycja Anna Glogowski 2,   
  • Antonia Cugliari 1,   
  • Fabiana Trombetti 1,   
  • Micaela Fabbri 1,   
  • Cristina Algieri 3,*

Received: 08 May 2026 | Revised: 10 Jun 2026 | Accepted: 06 Jul 2026 | Published: 09 Jul 2026

Abstract

Mitochondria are multifunctional organelles that integrate bioenergetics with innate immune regulation, acting as central hubs of immunometabolic control. Beyond ATP production, mitochondrial dysfunction promotes the release of mitochondrial damage-associated molecular patterns (mtDAMPs), among which mitochondrial DNA (mtDNA) represents a key inflammatory signal due to its bacterial features, susceptibility to oxidative damage, and capacity to activate innate immune pathways. Once displaced from mitochondria, mtDNA engages the cGAS–STING axis, the NLRP3 inflammasome, and Toll-like receptor 9 signaling, thereby driving type I interferon responses, NF-κB activation, and IL-1β maturation in sterile inflammatory conditions. A critical determinant of mtDNA release is the mitochondrial permeability transition pore (mPTP), a Ca2+- and ROS-sensitive channel whose sustained opening promotes mitochondrial depolarization, structural collapse, and escape of oxidized mtDNA into cytosolic and extracellular compartments. In parallel, mitochondrial quality control (MQC) systems, including mitophagy and mitochondrial-derived vesicles (MDVs), regulate the selective sequestration and removal of damaged mitochondrial components. MDVs constitute an early and highly selective MQC pathway that traffics oxidized proteins, lipids, and in some contexts nucleic acids toward lysosomal or extracellular destinations. The balance between mPTP-dependent mitochondrial rupture, mtDNA oxidation and release, and MDV-mediated selective cargo sorting defines whether mitochondrial stress is resolved through adaptive quality control or converted into inflammatory signaling. Importantly, MDVs may either limit inflammation by removing damaged mitochondrial components or contribute to immune modulation depending on cargo composition and cellular context. Together, the mPTP-mtDNA-MDV axis emerges as an integrated framework linking mitochondrial integrity to innate immune activation, immunometabolic rewiring, and sterile inflammation, providing mechanistic insight into how mitochondrial stress is translated into inflammatory disease pathways.

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DOI
10.53941/ti.2026.100010
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Volume 1, Issue 1
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Nesci, S.; Glogowski, P. A.; Cugliari, A.; Trombetti, F.; Fabbri, M.; Algieri, C. Mitochondrial DNA and Mitochondrial-Derived Vesicles as Immunometabolic Modulators of Innate Immunosurveillance through Control of the Mitochondrial Permeability Transition Pore. Translational Insights 2026, 1 (1), 10. https://doi.org/10.53941/ti.2026.100010.
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