Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8 + T cell formation

• Published in: Science immunology 2023-09, Vol.8 (87), p.eadf7579-eadf7579
• Main Authors: Franco, Fabien, Bevilacqua, Alessio, Wu, Ruey-Mei, Kao, Kung-Chi, Lin, Chun-Pu, Rousseau, Lorène, Peng, Fu-Ti, Chuang, Yu-Ming, Peng, Jhan-Jie, Park, Jaeoh, Xu, Yingxi, Cassotta, Antonino, Yu, Yi-Ru, Speiser, Daniel E., Sallusto, Federica, Ho, Ping-Chih
• Format: Article
• Language: English
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.adf7579

Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson’s disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8 + T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson’s disease patients have a reduced frequency of CD8 + memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8 + T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell–mediated antiviral responses in Parkinson’s disease patients. Parkin and NIX coordinate mitochondrial dynamics and function to prevent cell death during memory T cell formation. During an immune response, T cells rely on mitochondria to support their evolving metabolic demands. Maintenance of mitochondrial health requires removal of damaged mitochondria via mitophagy, which can occur through PINK1/Parkin- or BNIP3L/NIX-mediated pathways. Using peripheral blood from patients with Parkinson’s disease and LCMV-infected mice, Franco et al . examined the function of mitochondrial quality control in memory T cell responses. Patients with Parkinson’s disease, which is associated with impairments in mitophagy, had fewer CD8 + memory T cells and impaired SARS-CoV-2–specific responses after vaccination. In LCMV-infected mice, Parkin suppressed VDAC1-dependent apoptosis of memory T cells, whereas NIX restrained ferroptosis by preventing metabolic dysfunction. These results demonstrate that key pathways of mitophagy support memory T cell responses by limiting distinct forms of cell death. —Claire Olingy