Peroxisomes are critical for a unique metabolic demand and survival of alveolar macrophages
Tissue-resident macrophages (TRMs) populate throughout various tissues, and their homeostatic metabolism is heavily influenced by these microenvironments. Peroxisomes are organelles that contribute to lipid metabolism. However, the involvement of these organelles in the bioenergetics of TRMs remains undetermined. We conducted a developmental screen of TRMs using a conditional peroxisomal biogenesis factor 5 (Pex5) knockout mouse model that lacks functional peroxisomes in all immune cell subsets. Pulmonary alveolar macrophages (AMs) appeared as the only subset of TRMs that required functional peroxisomes for their development. Pex5 deficiency resulted in reduced AM survival due to increased sensitivity to lipotoxicity, in line with an excess accumulation of ceramides. The absence of peroxisomes had a significant effect on overall mitochondrial fitness and altered their metabolic program, allowing them to engage in glycolysis in addition to oxidative phosphorylation. Our results revealed that AMs have a unique metabolic regulation, where peroxisomes play a central role in their homeostatic development and maintenance.
Authors
- Jonathan Muri (ORCID: https://orcid.org/0000-0002-6476-3766)
- Huan Liu (ORCID: https://orcid.org/0000-0001-9336-2067)
- Ivan Berest (ORCID: https://orcid.org/0000-0001-7607-9163)
- Alaa Othman (ORCID: https://orcid.org/0000-0002-0092-5594)
- Fengqi Li (ORCID: https://orcid.org/0000-0002-2119-4380)
- Basak Corak (ORCID: https://orcid.org/0000-0002-8255-9793)
- Mai Matsushita (ORCID: https://orcid.org/0000-0001-5693-461X)
- Jovana Cupovic
- Werner Josef Kovacs (ORCID: https://orcid.org/0000-0002-4440-4344)
- Joerg M. Buescher (ORCID: https://orcid.org/0000-0002-6547-0076)
- Sabine Werner (ORCID: https://orcid.org/0000-0001-7397-8710)
- Mauro Corrado (ORCID: https://orcid.org/0000-0002-0617-3274)
- Manfred Köpf (ORCID: https://orcid.org/0000-0002-0628-7140)
- Nicola Zamboni (ORCID: https://orcid.org/0000-0003-1271-1021)
Institutions
- ETH Zurich (CH)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-25
- DOI
- https://doi.org/10.1016/j.celrep.2025.115623
- Citations
- 3
- Primary Topic
- Peroxisome Proliferator-Activated Receptors
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Eidgenössische Technische Hochschule Zürich