Mitochondrial calcium uniporter complex controls T‑cell‑mediated immune responses

ABSTRACT: Sustained and balanced calcium (Ca2+) increase upon T-cell receptor activation is a fundamental process that regulates essential T-cell functions including proliferation, clonal expansion and cytokine secretion. In this context, mitochondria play an important role and take up Ca2+ to support the elevated bioenergetic demands. Accordingly, alterations in the protein machinery that regulates mitochondrial Ca2+ (mCa2+) flux across the inner mitochondrial membrane; the mitochondrial calcium uniporter (MCU) complex, could be implicated in T-cell immunity. However, the exact role of mCa2+, and thus MCU in T-cells is not fully understood. Here, we show that upon activation of primary human CD4+ T-cells, the MCU complex undergoes a time-dependent compositional rearrangement that causes elevated mCa2+ uptake and increased mitochondrial bioenergetic output. Transcriptome and proteome analyses of naive and effector CD4+ T-cells reveal molecular determinants involved in mitochondrial and T-cell functional reprograming. Moreover, they identify genes, proteins and signaling pathways controlled by mitochondrial Ca2+ homeostasis i.e. the MCU. MCUa knockdown (KD) diminishes mCa2+, mitochondrial respiration and ATP production as well as T-cell invasion and cytokine secretion. In vivo, downregulation of MCUa in rat CD4+ T-cells suppresses autoimmune responses in a multiple sclerosis model of inflammatory experimental autoimmune encephalomyelitis (EAE). In summary, our findings imply that mCa2+ uptake through MCU is essential for proper T-cell function and is involved in autoimmunity. Specific MCU inhibitors targeting T-cells could be beneficial for autoimmune suppression and control of immune system dysregulation.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell

SUBMITTER: Prerana Wagle  

LAB HEAD: Jan Riemer

PROVIDER: PXD048682 | Pride | 2024-10-24

REPOSITORIES: Pride