MassIVE MSV000097528

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GNPS - Assessing effect of iron deficiency (+/- Aspartate) on CD8+ T cell metabolism

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Description

Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogated how physiologically low iron availability affected CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation did not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalled proliferation (without influencing cell viability), altered histone methylation status, gene expression, and disrupted mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle was limited and partially reversed to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Surprisingly and despite aberrant TCA cycling, aspartate was increased in stalled iron deficient CD8+ T-cells but was not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescued expansion and some functions of severely iron-deficient CD8+ T-cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency. [doi:10.25345/C56Q1SV8K] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Iron, CD8+ t cell, aspartate, metabolism ; DatasetType:Metabolomics

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Principal Investigators:
(in alphabetical order) 		Alexander Drakesmith, University of Oxford, United Kingdom
Submitting User: bmarzullo
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