PMID- 32686869 OWN - NLM STAT- MEDLINE DCOM- 20210824 LR - 20210824 IS - 1440-1711 (Electronic) IS - 0818-9641 (Print) IS - 0818-9641 (Linking) VI - 98 IP - 7 DP - 2020 Aug TI - Lipopolysaccharide promotes Drp1-dependent mitochondrial fission and associated inflammatory responses in macrophages. PG - 528-539 LID - 10.1111/imcb.12363 [doi] AB - 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 marrow-derived macrophages (BMMs) and human monocyte-derived macrophages. In BMMs, this response requires Toll-like 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 dynamin-related protein 1 (Drp1) GTPase that promotes mitochondrial fission is enriched on mitochondria in LPS-activated macrophages and is required for the LPS-mediated 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. LPS-induced S656 dephosphorylation was abrogated in MyD88-deficient BMMs, suggesting that this post-translational modification is particularly important for Tlr4-inducible fission. Pharmacological or genetic targeting of Tlr4-inducible fission had selective effects on inflammatory mediator production, with LPS-inducible 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 MyD88-dependent activation of Drp1, leading to inducible mitochondrial fission and subsequent inflammatory responses in macrophages. CI - (c) 2020 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. FAU - Kapetanovic, Ronan AU - Kapetanovic R AUID- ORCID: 0000-0002-2908-1014 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - Afroz, Syeda Farhana AU - Afroz SF AUID- ORCID: 0000-0001-6066-3445 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - Ramnath, Divya AU - Ramnath D AUID- ORCID: 0000-0002-1935-9043 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - Lawrence, Grace Mep AU - Lawrence GM AUID- ORCID: 0000-0001-9764-1194 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - Okada, Takashi AU - Okada T AUID- ORCID: 0000-0002-7366-3767 AD - The Mitochondrial Genetics Group, Robinson Research Institute, School of Medicine, Adelaide Health and Medical Sciences Building, The University of Adelaide, Adelaide, SA, 5005, Australia. FAU - Curson, James Eb AU - Curson JE AUID- ORCID: 0000-0002-4672-3357 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - de Bruin, Jost AU - de Bruin J AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - Fairlie, David P AU - Fairlie DP AUID- ORCID: 0000-0002-7856-8566 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - Schroder, Kate AU - Schroder K AUID- ORCID: 0000-0001-9261-3805 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. FAU - St John, Justin C AU - St John JC AUID- ORCID: 0000-0002-3993-1449 AD - The Mitochondrial Genetics Group, Robinson Research Institute, School of Medicine, Adelaide Health and Medical Sciences Building, The University of Adelaide, Adelaide, SA, 5005, Australia. FAU - Blumenthal, Antje AU - Blumenthal A AUID- ORCID: 0000-0003-3673-7015 AD - The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, 4102, Australia. FAU - Sweet, Matthew J AU - Sweet MJ AUID- ORCID: 0000-0002-0406-8139 AD - Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. AD - Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, 4072, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200720 PL - United States TA - Immunol Cell Biol JT - Immunology and cell biology JID - 8706300 RN - 0 (Lipopolysaccharides) RN - 0 (Mitochondrial Proteins) RN - 0 (Myd88 protein, mouse) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - EC 3.6.5.5 (Dnm1l protein, mouse) RN - EC 3.6.5.5 (Dynamins) SB - IM MH - Animals MH - Cells, Cultured MH - Dynamins/*metabolism MH - Fibroblasts MH - Humans MH - *Lipopolysaccharides MH - Macrophages/*immunology MH - Mice MH - *Mitochondrial Dynamics MH - Mitochondrial Proteins MH - Myeloid Differentiation Factor 88 MH - Toll-Like Receptor 4 PMC - PMC7497224 OTO - NOTNLM OT - Dynamin-related protein 1 OT - Toll-like receptor OT - lipopolysaccharide OT - macrophage OT - mitochondrial dynamics OT - mitochondrial fission COIS- All authors declare that they have no conflict of interest. EDAT- 2020/07/21 06:00 MHDA- 2021/08/25 06:00 PMCR- 2020/09/17 CRDT- 2020/07/21 06:00 PHST- 2020/04/08 00:00 [received] PHST- 2020/05/21 00:00 [revised] PHST- 2020/05/26 00:00 [accepted] PHST- 2020/07/21 06:00 [pubmed] PHST- 2021/08/25 06:00 [medline] PHST- 2020/07/21 06:00 [entrez] PHST- 2020/09/17 00:00 [pmc-release] AID - IMCB12363 [pii] AID - 10.1111/imcb.12363 [doi] PST - ppublish SO - Immunol Cell Biol. 2020 Aug;98(7):528-539. doi: 10.1111/imcb.12363. Epub 2020 Jul 20.