Herein, we found that the excessive ncfDNA and mtcfDNA in COVID-19 plasma caused the overproduction of mtROS in kidney tubule cells via TLR9, which might contribute to a positive feedback loop that contributes to the pathogenesis of COVID-19 multiple organ failure; that is, tissue injury leads to the release of cfDNA, which then acts on other tissue types via TLR9 to trigger additional tissue injury. Here, TLR9 is linked to Multiple Organ Failure.