Cardiolipin Loss Triggers Colitis in Mice, Shortening Lifespan by 7 Months via Treg Stress Signaling
Updated
Updated · Nature.com · May 18
Cardiolipin Loss Triggers Colitis in Mice, Shortening Lifespan by 7 Months via Treg Stress Signaling
2 articles · Updated · Nature.com · May 18
PTPMT1-deficient mice developed gut inflammation and died earlier, with median lifespan falling to 90 weeks from 128 weeks as cardiolipin loss in T cells undermined regulatory T-cell function.
Helicobacter exposure sharply worsened disease: H. hepaticus-colonized mutant mice failed to gain weight, developed colitis, and accumulated inflammatory monocytes and neutrophils because Treg cells could not mount normal tolerance.
Mechanistically, cardiolipin deficiency disrupted mitochondrial structure, respiration and translation in Treg cells, activating a maladaptive integrated stress response marked by ATF4 and CHOP and reducing FOXP3-linked suppressive programs.
Blocking that stress pathway partly reversed the damage—CHOP deletion rescued lifespan and gut pathology, while daily ISRIB at 5 mg/kg delayed autoimmunity in severe Treg-specific knockout mice.
The study also linked the pathway to Barth syndrome: TAZ-deficient mice showed Treg defects and inflammation, and more than 60% of 115 registry patients reported gastrointestinal disorders alongside ISR-associated immune abnormalities.
A key lipid acts as the master switch for gut immunity. What happens when this fundamental switch is broken?
Can targeting a single mitochondrial lipid become the next breakthrough therapy for inflammatory bowel disease?
Cardiolipin Deficiency in T Cells Identified as Key Driver of Gut Inflammation and Metabolic Disease: Implications for Precision Therapies
Overview
A major study published in May 2026 revealed that the loss of cardiolipin—a key mitochondrial phospholipid—in T cells leads to impaired metabolic function, which causes a breakdown in gut immune tolerance. This breakdown triggers severe gut inflammation and the development of colitis, ultimately resulting in a much shorter lifespan in mice. By identifying cardiolipin loss in T cells as a critical metabolic vulnerability, the research highlights how immune cell metabolism directly impacts gut health and opens new possibilities for understanding and treating inflammatory diseases.