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

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.

Automated summary

Mitophagy plays a crucial role in the formation of memory CD8(+) T cells and T cell-mediated antiviral responses. Deficits in mitophagy lead to reduced frequency of CD8(+) memory T cells in Parkinson's disease patients and hinder the formation of memory T cells upon vaccination against COVID-19. Regulators of mitophagy, such as Parkin and NIX, are up-regulated by interleukin-15 (IL-15) to support memory T cell formation. Parkin suppresses apoptosis in memory T cells, while NIX prevents metabolic dysfunction and counteracts ferroptosis resulting from impaired mitophagy.