Disassembly of electron transport chain complexes drives macrophage TLR responses by reprogramming metabolism and translation

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.

Name thesis:degree_name

Doctoral

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Biology

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2020

Author dc:creator

• Su, Yang

Advisor dc:contributor.advisor

• Jianzhu Chen.

• Biology.

Statement dc:rights

• 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1721.1/127139

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/127139