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Jianzhu Chen. Su, Yang Massachusetts Institute of Technology. Department of Biology. Massachusetts Institute of Technology. Department of Biology 2020-09-03T17:48:56Z 2020-09-03T17:48:56Z 2020 2020 https://hdl.handle.net/1721.1/127139 1191838675 Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, May, 2020 Cataloged from the official PDF of thesis. Includes bibliographical references. Metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis is a key feature of inflammatory response in macrophages, but how this switch occurs in response to inflammatory signals and how it precisely contributes to macrophage function is still obscure. Here we show that stimulation of macrophages through Toll-like receptors (TLR) disrupts the assembly of mitochondrial electron transfer chain (ETC) complexes I-V, leading to the metabolic switch by inhibiting OxPhos and activating HIF-1[alpha]-dependent glycolysis. Disassembly of ETC complexes influences the global metabolic status of macrophages not only by inducing glycolysis but also largely by inducing the reprogramming of cellular translational capacity via mTORC1 and ATF4, leading to enhanced global translation rate, cell growth, and production of inflammatory cytokines. Inhibition of OxPhos via myeloid-specific knockout of OPA1, which stimulates ETC complex assembly, exacerbates sepsis in mice while inhibition of mTORC1 reverses this effect. These findings reveal that disassembly of ETC complexes underlies macrophage metabolic switch and inflammatory responses and may be a conserved pathway to reprogram cellular anabolism and function. by Yang Su. Ph.D. Ph.D. Massachusetts Institute of Technology, Department of Biology 108 pages eng Massachusetts Institute of Technology MIT theses may be protected by copyright. Please reuse MIT thesis content according to the MIT Libraries Permissions Policy, which is available through the URL provided. http://dspace.mit.edu/handle/1721.1/7582 Biology. Disassembly of electron transport chain complexes drives macrophage TLR responses by reprogramming metabolism and translation Thesis application/pdf 2020-09-03T17:48:55Z Publication Doctoral Bio unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="e07d5f6c-116a-496c-bb2b-86604062dba4"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Disassembly of electron transport chain complexes drives macrophage TLR responses by reprogramming metabolism and translation</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2020</PublicationDate> <Authors> <Author> <DisplayName>Su, Yang</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Biology.</Keyword> <Abstract>Metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis is a key feature of inflammatory response in macrophages, but how this switch occurs in response to inflammatory signals and how it precisely contributes to macrophage function is still obscure. Here we show that stimulation of macrophages through Toll-like receptors (TLR) disrupts the assembly of mitochondrial electron transfer chain (ETC) complexes I-V, leading to the metabolic switch by inhibiting OxPhos and activating HIF-1[alpha]-dependent glycolysis. Disassembly of ETC complexes influences the global metabolic status of macrophages not only by inducing glycolysis but also largely by inducing the reprogramming of cellular translational capacity via mTORC1 and ATF4, leading to enhanced global translation rate, cell growth, and production of inflammatory cytokines. Inhibition of OxPhos via myeloid-specific knockout of OPA1, which stimulates ETC complex assembly, exacerbates sepsis in mice while inhibition of mTORC1 reverses this effect. These findings reveal that disassembly of ETC complexes underlies macrophage metabolic switch and inflammatory responses and may be a conserved pathway to reprogram cellular anabolism and function.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>