Mitochondrial DNA-driven intercellular communication networks in post-infarction ventricular remodeling: the three-threshold model of cGAS-STING activation

Figures

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  Figure 1. The three-threshold model of mtDNA-cGAS-STING activation. Left panel (release threshold): mtDNA leakage from mitochondria is controlled by mitophagy (PINK1/Parkin, green upward arrow) and oxidative modification (8−OHdG, yellow lightning). Middle panel (transmission threshold): Intercellular mtDNA transfer occurs via three major carriers – naked mtDNA, Ambra1+ sEVs, and intact mitochondria – whose efficiency depends on vesicle protection, uptake efficiency, and endosomal escape. Right panel (activation threshold): In recipient cells (macrophage shown), STING (purple) translocate from the ER to the Golgi, activating TBK1/IRF3/NF−κB. Different cell types exhibit distinct activation thresholds (macrophages: low; fibroblasts: high). Bottom: The three thresholds are interconnected by positive feedback loops, as indicated by bidirectional orange arrows. Solid arrows indicate well−established pathways; dashed arrows indicate proposed mechanisms that require experimental confirmation.

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  Figure 2. Four modes of intercellular mtDNA transfer and threshold matching. The four quadrants are arranged by increasing transmission threshold (top-left to bottom-right). Background colors indicate time windows: acute phase (light red, 0–3 days), subacute phase (light yellow, 3–7 days), chronic phase (light blue, >7 days). Mode 2: Cardiomyocytes release Ambra1+ sEVs delivering high-concentration mtDNA to fibroblasts, overcoming their high activation threshold via pulse release (subacute phase). Mode 3: Activated fibroblasts shed mt-sEVs that activate macrophages via NLRP3, amplifying inflammation (chronic phase). Mode 1: Naked mtDNA from damaged cardiomyocytes triggers macrophage STING activation, initiating sterile inflammation (acute phase). Mode 4: Intact mitochondria from necrotic cells activate endothelial cells via IFI16-STING, promoting vascular inflammation (severe injury). Bottom scatter plot: Each mode’s transmission threshold plotted against the recipient cell’s activation threshold; the dashed diagonal line illustrates threshold matching. The indicated modes represent the predominant transfer pathways during each time window; however, concurrent or overlapping transfer modes…

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  Figure 3. Positive feedback network among pathological effects driving threshold downregulation. Four pathological effects (inflammation, fibrosis, electrical remodeling, and vascular dysfunction) are interconnected by arrows indicating mutual amplification. Each effect reduces the release, transmission, and (except for fibrosis) activation thresholds, as indicated by downward arrows. The central circular arrow denotes the self-accelerating nature of the network. Once the three thresholds fall below a critical point, post-infarction remodeling becomes irreversible. Detailed mechanisms are described in Sections 5.1–5.4. The interconnections are based on indirect evidence; direct experimental proof of each cross−talk direction is lacking.