Iron deficiency causes aspartate-sensitive metabolic dysregulation in CD8+ T-cells

Iron is an irreplaceable co-factor for important enzyme systems, and iron deficiency is the most common micronutrient deficiency worldwide. How iron deprivation influences normal cellular function remains poorly characterised. Using activated CD8+ T-cells as a model for dividing cells we show iron restriction causes specific and broad-acting metabolic defects. Iron scarcity altered gene expression, stalled proliferation and disrupted mitochondrial redox control.  TCA cycle was partially redirected to a reductive trajectory, depleting malate, fumarate and α-ketoglutarate, while the repressive H3K27me3 histone mark was maintained. Surprisingly, aspartate, which is crucial for dividing cells, was increased in stalled iron deficient cells. However, aspartate was not utilised cytosolically, suggesting trapping in depolarised mitochondria. Exogenous aspartate markedly rescued proliferation and function of iron-deprived T-cells, increasing ATP and decreasing H3K27me3. Therefore, iron scarcity creates a metabolic bottleneck that impairs cell division and function, but which can be bypassed without iron by resupplying biochemical processes with aspartate.