Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut
Abstract Loss of host–microbiota balance promotes gut inflammation, colitis and inflammatory bowel disease. Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (T reg ) cells to preserve gut–immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired T reg cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs T reg cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 ΔT mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut–immune homeostasis and dictates outcome in pathobiont infections.
Authors
- Theodoros Georgomanolis (ORCID: https://orcid.org/0000-0002-4066-9257)
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Sara Cogliati (ORCID: https://orcid.org/0000-0002-0374-3489)
- Daniel Martínez‐Martínez (ORCID: https://orcid.org/0000-0001-8468-1357)
- Maaike Jacobs (ORCID: https://orcid.org/0000-0002-0292-7219)
- Farina Schneider
- Filipe Cabreiro (ORCID: https://orcid.org/0000-0002-3696-4843)
- Annamaria Regina (ORCID: https://orcid.org/0000-0003-2041-2320)
- Elena Potenza (ORCID: https://orcid.org/0000-0002-3323-1775)
- David E. Sanin (ORCID: https://orcid.org/0000-0003-0188-7267)
- Erika L. Pearce (ORCID: https://orcid.org/0000-0001-5592-5439)
- Francesca Solagna (ORCID: https://orcid.org/0000-0001-6607-2291)
- Niloufar Safinia (ORCID: https://orcid.org/0000-0002-8885-1082)
- Matteo Villa (ORCID: https://orcid.org/0000-0003-2684-0596)
- Ana Sagrera Aparisi
- Milica Popović (ORCID: https://orcid.org/0000-0002-8762-6967)
- Mauro Corrado (ORCID: https://orcid.org/0000-0002-0617-3274)
- Edward J. Pearce (ORCID: https://orcid.org/0000-0003-1001-9656)
- Borko Amulic (ORCID: https://orcid.org/0000-0002-8518-8393)
- Chrysanthi Moschandrea
- Claire Pearson
- L Trojahn
- Carien Niessen
- Fiona Powrie
- Agnieszka M. Kabat
- Paulina Pfelzer
- Elena Crespo
- Irma Alibashikj
- Malkon Sanchez Estrada
- Dehui Chang (ORCID: https://orcid.org/0000-0002-0864-9141)
- Sara Gjurgji
- Jessica Buechel
Institutions
- TH Köln - University of Applied Sciences (DE)
- Bloomberg (United States) (US)
- Johns Hopkins University (US)
- King's College - North Carolina (US)
- University of Cologne (DE)
- King's College London (GB)
- Medical University of Graz (AT)
- University of Bristol (GB)
- University of Oxford (GB)
- Sidney Kimmel Cancer Center (US)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Centro de Biología Molecular Severo Ochoa (ES)
- King's College Hospital (GB)
- University Hospital Cologne (DE)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- Sidney Kimmel Comprehensive Cancer Center (US)
- Imperial College London (GB)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-05-18
- DOI
- https://doi.org/10.1038/s42255-026-01533-9
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft