Targeted Restoration of Mitophagy Reinvigorates Aged Hematopoietic Stem Cells

Abstract

Aims: Aging-related functional decline in hematopoietic stem cells (HSCs) is closely associated with mitochondrial dysfunction and impaired mitophagy. This study aimed to investigate whether targeted restoration of mitophagy via the myeloid cell leukemia 1 (MCL-1)/light chain 3A pathway could rejuvenate aged HSCs and improve their regenerative capacity. Results: We identified MCL-1 as the most highly expressed mitophagy receptor in aged HSCs. Treatment with UMI-77, a selective MCL-1 agonist, significantly enhanced mitophagy, reduced mitochondrial mass, improved mitochondrial membrane potential, and reduced reactive oxygen species levels in aged HSCs both in vitro and in vivo . Single-cell RNA sequencing revealed that UMI-77 upregulated mitophagy-related genes ( Sqstm1 , Fundc1 , Bnip3 ) and restored stemness signatures in long-term HSCs. Transplantation assays demonstrated that UMI-77-treated aged HSCs exhibited superior hematopoietic reconstitution capacity compared with those from control mice. However, this intervention also increased the proportion of myeloid-biased CD150 high HSCs, a hallmark of aging. Conclusion: Targeted mitophagy restoration via MCL-1 activation improves mitochondrial fitness and stemness in aged HSCs but does not reverse myeloid bias. These findings highlight mitophagy enhancement as a viable therapeutic approach, while suggesting combinatorial strategies may be needed to fully restore lineage balance in aging hematopoiesis. Antioxid. Redox Signal. 00, 000–000.