Mitochondrial Metabolism: a Druggable Driver of Stem Cell Fate in Ageing and Disease

Ageing of Hematopoietic Stem Cells (HSCs) is characterised by myeloid bias at the expense of lympho/erythroid commitment and predisposes to anemia, immune compromise and malignancy. To be able to correct this, we need to understand the drivers and level of plasticity of different stem cell states.

Recently I discovered that metabolism and fate decisions are tightly linked in HSCs (Mansell et al, Cell Stem Cell, 2021), by showing that mitochondrial membrane potential (MMP) can be used to prospectively isolate young-like HSCs from old mice: HSCs with high MMP, that become sparse with age, had transcriptional and functional features of young HSCs, including enrichment for lympho/erythroid potential.

Chemical enhancement of MMP in old mice through mitoquinol treatment caused partial reversal of myeloid-bias and rescue of lymphoid and erythroid production.

This proposal builds on this new line of investigation linking mitochondrial metabolism to lineage fate in the context of steady state hematopoieisis, hematopoietic ageing and disease.

The first aim is to map out the relationship between metabolic state and lineage fate of cells occupying the top of the hematopoietic hierarchy.

The second aim is to assess, at the single cell level, the biological youthfulness of old HSCs with high MMP as well as the metabolic plasticity of old HSCs.

Finally, I will investigate if mitochondrial potentiation therapy might be clinically applicable as supportive therapy after chemotherapy.