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Mitochondrial Impairment Mediates Cytolysis in Anthrax Lethal Toxin-Treated Murine Macrophages

Abdelkrim Alileche, Raynal C Squires, Stefan M Muehlbauer, Michael P. Lisanti and Jürgen Brojatsch

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Numerous early events in anthrax lethal toxin (LT)-mediated cell killing have been described, including uptake of LT and MAPKK cleavage. However, critical downstream events in LT killing remain to be identified. In this study we show that LT cause mitochondrial dysfunction in murine J774A.1 macrophages, as indicated by a continuous drop in both mitochondrial membrane potential and SDH activity over 90 min of LT exposure. This was further supported by ultrastructural analysis revealing LT-induced swelling of mitochondria. Mitochondrial impairment and cytolysis were controlled by proteasomes: Proteasome inhibitors restored mitochondrial activity and rescued cells from cytolysis, even when added immediately prior to membrane perturbation, suggesting a link between mitochondrial impairment and cytolysis. The addition of KCl delayed LT-mediated cytolysis, but could not block mitochondrial impairment or rescue cells. KCl treatment precluded events linked to cytolysis, including a precipitous drop in ATP levels and ubiquitinated proteins, revealing that they are epiphenomena in LT killing. This is the first study that indicates mitochondrial targeting by anthrax lethal toxin. We present evidence that mitochondrial dysfunction and membrane perturbation are key events in LT killing, and are controlled by proteasomes and KCl.

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