NIX-Mediated Mitophagy Promotes Effector Memory Formation in Antigen-Specific CD8+ T Cells

Abstract

Summary: Autophagy plays a critical role in the maintenance of immunological memory. However, the molecular mechanisms involved in autophagy-regulated effector memory formation in CD8+ T cells remain unclear. Here we show that deficiency in NIX-dependent mitophagy leads to metabolic defects in effector memory T cells. Deletion of NIX caused HIF1α accumulation and altered cellular metabolism from long-chain fatty acid to short/branched-chain fatty acid oxidation, thereby compromising ATP synthesis during effector memory formation. Preventing HIF1α accumulation restored long-chain fatty acid metabolism and effector memory formation in antigen-specific CD8+ T cells. Our study suggests that NIX-mediated mitophagy is critical for effector memory formation in T cells. : Gupta et al. demonstrate that mitophagy mediated by NIX, a mitochondrial outer membrane protein, plays a critical role in CD8+ T cell effector memory formation by regulating mitochondrial superoxide-dependent HIF1α protein accumulation and fatty acid metabolism. These findings elucidate the molecular mechanisms regulating T cell effector memory formation against viruses. Keywords: NIX, mitophagy, autophagy, CD8+ T cells, effector memory cells, HIF1α, fatty acid metabolism, long-chain fatty acid oxidation, short/branched-chain fatty acid oxidation, mitochondrial superoxide