Editors' ChoiceHost-Pathogen Interactions

Pathogen-induced mitochondrial fragmentation

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Science Signaling  03 Oct 2017:
Vol. 10, Issue 499, eaaq0807
DOI: 10.1126/scisignal.aaq0807

Legionella pneumophila promotes activation of the mitochondrial fission machinery to metabolically reprogram host macrophages.

Intracellular pathogens often target host metabolic pathways to ensure optimal conditions for replication. After being internalized by host macrophages, the intracellular pathogen Legionella pneumophila is sequestered in Legionella-containing vacuoles (LCVs), from whence it injects effector proteins into the host cytoplasm using a type 4 secretion system (T4SS). Escoll et al. performed live imaging of infected primary human monocyte–derived macrophages (hMDMs) and observed that LCVs interacted dynamically with mitochondria, even if the bacteria lacked a functional T4SS. Infection also promoted mitochondrial fragmentation in a manner that depended on a L. pneumophila Ran GTPase–activating T4SS effector protein that the authors named MitF. Depleting cells of Ran, Ran-binding protein 2 (RanBP2), or dynamin 1–like protein (DNM1L, also called Drp1) reduced LCV-induced mitochondrial fragmentation and L. pneumophila replication. DNM1L is a GTPase that promotes fission when recruited to the mitochondrial membrane, and L. pneumophila infection indeed promoted the accumulation of DNM1L on mitochondria in a T4SS-dependent manner. Ran and RanBP2 are involved in regulating actin dynamics, and RanBP2 is also implicated in the regulation of DNM1L activity; stimulating either or both of these functions could contribute to mitochondrial fission (see Kozjak-Pavlovic et al.). Mitochondrial fragmentation is often considered an indicator of cell death; however, L. pneumophila infection did not induce other morphological or biochemical markers of cell death. Infection did, however, alter mitochondrial function, causing an increase in glycolysis and a decrease in oxidative phosphorylation. This is consistent with the cells undergoing a metabolic shift similar to the Warburg effect in cancer cells, in which cells show increased glycolysis and reduced oxidative phosphorylation. Pharmacologically interfering with glycolysis impeded L. pneumophila replication, which may explain the previous observation that L. pneumophila replicates more effectively in cancer cells than in nontransformed cells. The involvement of DNM1L and the failure to induce apoptotic markers differentiate L. pneumophila infection from other intracellular pathogens that also affect mitochondrial architecture (see Kozjak-Pavlovic et al.).

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