Study summary · research use only
BAM15 treats mouse sepsis and kidney injury, linking mortality, mitochondrial DNA, tubule damage, and neutrophils
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this mouse sepsis study using cecal ligation and puncture (CLP), the authors examined BAM15, a mitochondrial uncoupler, injected at 0, 6, or 12 hours after CLP alongside fluids and antibiotics. BAM15 was associated with reduced mortality even at 12 hours, and with reduced kidney damage and splenic apoptosis. Plasma and urinary mitochondrial DNA (mtDNA) rose after CLP and fell after BAM15 at 0 or 6 hours. In vitro, septic serum increased mitochondrial ROS (mtROS) and mtDNA release from kidney tubule cells, which BAM15 prevented; BAM15 also decreased neutrophil apoptosis and mtDNA release, and neutrophil depletion counteracted these associations. Injecting mtDNA in vivo reproduced inflammation and kidney injury, which BAM15 prevented, while a large mtDNA dose reversed this. The authors describe BAM15 as linked to mtDNA via mtROS in sepsis.
Abstract
Sepsis pathogenesis is complex and heterogeneous; hence, a precision-medicine strategy is needed. Acute kidney injury (AKI) following sepsis portends higher mortality. Overproduction of mitochondrial ROS (mtROS) is a potential mediator of sepsis and sepsis-induced AKI. BAM15, a chemical uncoupler, dissipates mitochondrial proton gradients without generating mtROS. We injected BAM15 into mice at 0, 6, or 12 hours after cecal ligation and puncture (CLP), and these mice were treated with fluids and antibiotics. BAM15 reduced mortality, even after 12 hours, when mice were ill, and BAM15 reduced kidney damage and splenic apoptosis. Serial plasma and urinary mitochondrial DNA (mtDNA) levels increased after CLP and decreased after BAM15 administration (at 0 or 6 hours). In vitro septic serum proportionately increased mtROS overproduction and mtDNA release from kidney tubule cells, which BAM15 prevented. BAM15 decreased neutrophil apoptosis and mtDNA release; neutrophil depletion counteracted BAM15 benefits. Further, mtDNA injection in vivo replicated inflammation and kidney injury, which was prevented by BAM15. A large dose of exogenous mtDNA reversed protection by BAM15. We conclude that BAM15 is an effective preventive and therapeutic candidate in experimental sepsis and that BAM15 and mtDNA, a potential drug-companion diagnostic/drug-efficacy pair for clinical sepsis, are mechanistically linked via mtROS.
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