Autophagy-regulated mitochondrial inheritance controls early CD8 + T cell fate commitment

Journal article

T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.

Authors: Borsa, M; Lechuga-Vieco, AV; Kayvanjoo, AH; Jenkins, E; Yazicioglu, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Cell Biology
• Volume: 28
• Issue: 1
• Pages: 66-81
• Publication date: 2025-12-19
• Acceptance date: 2025-11-04
• DOI: 10.1038/s41556-025-01835-2
• EISSN: 1476-4679
• ISSN: 1465-7392
• Language: English