Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8 <sup>+</sup> T cell formation
Fabien Franco, Alessio Bevilacqua, Ruey-Mei Wu, Kung‐Chi Kao, Chun‐Pu Lin, Lorène Rousseau, Fu‐Ti Peng, Yu‐Ming Chuang, Jhan-Jie Peng, Jaeoh Park, Yingxi Xu, Antonino Cassotta, Yi-Ru Yu, Daniel E. Speiser, Federica Sallusto, Ping‐Chih Ho
Abstract
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.