2 research outputs found
Lipopolysaccharide promotes Drp1-dependent mitochondrial fission and associated inflammatory responses in macrophages
Mitochondria have a multitude of functions, including energy generation and cell signaling. Recent evidence suggests that mitochondrial dynamics (i.e. the balance between mitochondrial fission and fusion) also regulate immune functions. Here, we reveal that lipopolysaccharide (LPS) stimulation increases mitochondrial numbers in mouse bone marrowâderived macrophages (BMMs) and human monocyteâderived macrophages. In BMMs, this response requires Tollâlike receptor 4 (Tlr4) and the TLR adaptor protein myeloid differentiation primary response 88 (MyD88) but is independent of mitochondrial biogenesis. Consistent with this phenomenon being a consequence of mitochondrial fission, the dynaminârelated protein 1 (Drp1) GTPase that promotes mitochondrial fission is enriched on mitochondria in LPSâactivated macrophages and is required for the LPSâmediated increase in mitochondrial numbers in both BMMs and mouse embryonic fibroblasts. Pharmacological agents that skew toward mitochondrial fusion also abrogated this response. LPS triggered acute Drp1 phosphorylation at serine 635 (S635), followed by sustained Drp1 dephosphorylation at serine 656 (S656), in BMMs. LPSâinduced S656 dephosphorylation was abrogated in MyD88âdeficient BMMs, suggesting that this postâtranslational modification is particularly important for Tlr4âinducible fission. Pharmacological or genetic targeting of Tlr4âinducible fission had selective effects on inflammatory mediator production, with LPSâinducible mitochondrial fission promoting the expression and/or secretion of a subset of inflammatory mediators in BMMs and mouse embryonic fibroblasts. Thus, triggering of Tlr4 results in MyD88âdependent activation of Drp1, leading to inducible mitochondrial fission and subsequent inflammatory responses in macrophages.Ronan Kapetanovic, Syeda Farhana Afroz, Divya Ramnath, Grace MEP Lawrence, Takashi Okada, James EB Curson, Jost de Bruin, David P Fairlie, Kate Schroder, Justin C St John, Antje Blumenthal, Matthew J Swee