Mitochondrial DNA efflux as a potential amplifier of systemic inflammatory network rewiring in heart failure with preserved ejection fraction

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  Figure 1. Framework of the mtDNA-associated systemic inflammatory network in HFpEF. This figure illustrates the overall framework of an mtDNA-associated cross-organ inflammatory network in HFpEF. On the left is the mitochondrial structure, and mtDNA is released into the cytoplasm and extracellular environment under conditions of cellular stress or damage (“mtDNA release”). The released mtDNA spreads through the circulatory system (central arrow) and acts on multiple target organs. In the vascular system (middle part), mtDNA is recognized by the cGAS–STING pathway and TLR9 in endothelial cells, inducing vascular inflammatory responses, manifested as endothelial dysfunction and increased permeability (vascular inflammation). In the heart (upper part), mtDNA is perceived through the TLR9 and NLRP3 inflammatory pathway, leading to myocardial inflammation and functional impairment (myocardial damage). In the kidneys (right), mtDNA also activates the TLR9 and NLRP3 signaling pathways, promoting fibrosis and decreased filtration function (kidney dysfunction). In adipose tissue (below), mtDNA induces inflammatory responses through the cGAS–STING and NLRP3 pathways, causing metabolic disorders…

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  Figure 2. Hierarchical regulatory mechanism of mtDNA ejection. This figure illustrates the key mechanisms by which mitochondrial DNA (mtDNA) is released from the mitochondria and enters the extracellular environment, along with its various transport forms. The center of the figure depicts the mitochondrial structure, including the outer membrane and inner membrane, with mtDNA located in the mitochondrial matrix. Under stress conditions, the mitochondrial permeability transition pore (mPTP) opens (the illuminated area on the left), allowing mtDNA to move from the matrix into the intermembrane space and further migrate outward through increased inner membrane permeability. Subsequently, the outer membrane permeability is further enhanced through the formation of pores by the oligomerization of BAX/BAK and the rearrangement of voltage-dependent anion channels (VDAC) structure, thereby facilitating the entry of mtDNA into the cytoplasm. The released mtDNA can enter the extracellular environment through various pathways (below): some exist in a free form; some are packaged into EVs; in addition, in an inflammatory state, the neutrophil extracellular trap can capture and carry it. The arrows in…

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  Figure 3. Mechanism diagram of mtDNA trans-cellular propagation and systemic diffusion. This figure illustrates a proposed mechanism by which mtDNA may spread between multiple organs and participate in a positive feedback inflammatory network. Under mitochondrial damage or stress conditions, mtDNA is released from tissues such as the heart into the circulation system (left, “mtDNA release”). In the blood vessels, mtDNA exists in various forms, including free mtDNA, mtDNA encapsulated in EVs, and mtDNA carried by NETs (lower vascular region). The mtDNA in the circulation is taken up or recognized by cells in different organ tissues (heart, adipose tissue, and kidney modules).Within each tissue cell, mtDNA can be recognized by nucleic acid sensors such as Toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS), while NLRP3 acts as the downstream inflammasome platform to amplify the inflammatory output (activation), accompanied by enhanced inflammatory responses mediated by the STING pathway. These signals jointly promote local inflammatory responses and changes in cellular functions. The activation of inflammation further promotes the continuous release of mtDNA (“further mtDNA…

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  Figure 4. Hierarchical perception of mtDNA and mechanism of inflammatory signal amplification. This figure illustrates the mechanism by which mtDNA induces inflammatory responses and organ damage in different cell types through the cGAS–STING signaling pathway. From left to right in the figure are endothelial cells, macrophages, and cardiomyocytes. In each type of cell, mtDNA entering the cytoplasm is first recognized by the cyclic GMP-AMP synthase (cGAS) and catalyzes the production of the second messenger cGAMP. cGAMP further activates the STING protein on the endoplasmic reticulum, inducing conformational changes and downstream signal transduction. Activated STING recruits and activates related kinases, respectively, to initiate the NF-κB and IRF3 signaling pathways (in the middle). NF-κB and IRF3 then translocate to the nucleus, promoting the transcription of inflammatory-related genes. In the nucleus, these signaling pathways induce the expression of various inflammatory factors, including IL-1β, IL-6, and TNF (at the bottom). These inflammatory mediators produce different pathological effects in different cell types: endothelial dysfunction in endothelial cells; amplification of…