Organelle dysfunction upon asrij depletion causes aging-like changes in mouse hematopoietic stem cells

Aging of the blood system is characterized by increased hematopoietic stem cells (HSCs) and myeloid-biased differentiation leading to higher propensity for hematological malignancies. Unraveling cell-intrinsic mechanisms regulating HSC aging could aid reversal or slowing of aging. Asrij/OCIAD1 is an evolutionarily conserved regulator of hematopoiesis and governs mitochondrial, endosomal, and proteasomal function in mammalian stem cells. Asrij deletion in mice causes loss of HSC quiescence, myeloid skewing, reduced p53 and increased DNA damage, features attributed to aged HSCs. Mechanistically, Asrij controls p53 ubiquitination and degradation and AKT/STAT5 activation. Asrij localizes to endosomes and mitochondria. As decline in organelle structure and function are common hallmarks of aging, we asked whether Asrij regulates organelle function in aged HSCs. We find that chronologically aged wild-type (WT) HSCs had reduced Asrij levels. Expectedly, young asrij KO mice had reduced AcH4K16 levels; however, transcriptome analysis of KO HSCs showed a modest overlap of gene expression with aged WT HSCs. Further, analysis of organelle structure and function in asrij KO mice revealed significant changes, namely damaged mitochondria, elevated ROS; impaired endosomal trafficking seen by increased cleaved Notch1, reduced Rab5; and reduced 26S proteasome activity. Pharmacological correction of mitochondrial and proteasome activity in asrij KO mice restored HSC and myeloid cell frequencies. Furthermore, lysophosphatidic acid-induced Asrij upregulation in aged WT mice rescued mitochondrial and proteasome activity and restored HSC frequency. Our results highlight a new role for Asrij in preventing HSC aging by regulating organelle homeostasis and will help decipher organelle dynamics in HSC longevity.