Researchers here identify a common mechanism in the cellular responses to various forms of stress that appears to drive aspects of hematopoietic stem cell aging via impairment of mitochondrial function. Hematopoietic cells are responsible for generating immune cells and red blood cells. Aging produces alterations in the character and lineages of generated cells, contributing to dysfunction in the immune system and in platelet producing cells, among other issues. Suppressing some aspects of cellular stress responses, those that become maladaptive in the aged tissue environment, may prove to be useful as a basis for therapy. It nonetheless seems a poor alternative to instead repairing or otherwise addressing the forms of damage and dysfunction that provoke these excessive cell stress responses.
Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3–MLKL axis to induce age-related changes in HSCs.
The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death in HSCs but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
