YME1L1 is Dispensable for T Lymphocyte Activation Despite its Upregulation and Activity

Abstract

Mitochondrial dynamics are critical for T cell activation, differentiation, and survival. The inner mitochondrial membrane ATP-dependent metalloprotease YME1L1 regulates proteostasis and the processing of optic atrophy protein 1 (OPA1), thereby shaping mitochondrial cristae architecture and respiratory function in many cell types. Whether YME1L1 fulfils similar roles in lymphocytes remains unknown. Here, we examined YME1L1 function in T cells using conditional knockout mice lacking YME1L1 in lymphocytes (YME1L1{Delta}TB). YME1L1 expression increased upon T cell activation, yet its absence did not alter thymic development, peripheral T cell homeostasis, or the proportions of naive, memory, and regulatory subsets. T cell activation and proliferation in response to anti-CD3{varepsilon} stimulation were also unaffected. Mitochondrial parameters such as mass, membrane potential, and reactive oxygen species production, were largely preserved, with only modest, transient increases in oxidative stress detected in CD4 T cells lacking YME1L1. Electron microscopy revealed no major changes in mitochondrial size or roundness but showed increased cristae branching and reduced tortuosity, indicating subtle alterations in ultrastructure. Additionally, {gamma}{delta} T cells in YME1L1{Delta}TB mice exhibited a mild shift toward interferon-{gamma}-producing phenotypes at the expense of interleukin-17-producing subsets. Collectively, our data indicate that YME1L1, despite its requirement for OPA1 cleavage, is dispensable for T cell development and acute activation but may contribute to fine-tune mitochondrial architecture and {gamma}{delta} T cell effector programming. These findings highlight cell-type-specific redundancies in mitochondrial quality control and underscore the value of negative data in refining the understanding of mitochondrial regulation in immune cells.