Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis

Stefanie K. Wculek*, Ignacio Heras-Murillo, Annalaura Mastrangelo, Diego Mañanes, Miguel Galán, Verónica Miguel, Andrea Curtabbi, Coral Barbas, Navdeep S. Chandel, José Antonio Enríquez, Santiago Lamas, David Sancho*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


In vitro studies have associated oxidative phosphorylation (OXPHOS) with anti-inflammatory macrophages, whereas pro-inflammatory macrophages rely on glycolysis. However, the metabolic needs of macrophages in tissues (TMFs) to fulfill their homeostatic activities are incompletely understood. Here, we identified OXPHOS as the highest discriminating process among TMFs from different organs in homeostasis by analysis of RNA-seq data in both humans and mice. Impairing OXPHOS in TMFs via Tfam deletion differentially affected TMF populations. Tfam deletion resulted in reduction of alveolar macrophages (AMs) due to impaired lipid-handling capacity, leading to increased cholesterol content and cellular stress, causing cell-cycle arrest in vivo. In obesity, Tfam depletion selectively ablated pro-inflammatory lipid-handling white adipose tissue macrophages (WAT-MFs), thus preventing insulin resistance and hepatosteatosis. Hence, OXPHOS, rather than glycolysis, distinguishes TMF populations and is critical for the maintenance of TMFs with a high lipid-handling activity, including pro-inflammatory WAT-MFs. This could provide a selective therapeutic targeting tool.

Original languageEnglish (US)
Pages (from-to)516-530.e9
Issue number3
StatePublished - Mar 14 2023


  • cholesterol handling
  • immunometabolism
  • obesity
  • oxidative phosphorylation
  • pro-inflammatory macrophages
  • Tfam
  • tissue macrophages

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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