A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging

TLDR

Adult stem cell deterioration underlies aging‑related tissue decline, yet the mechanisms that maintain their metabolic homeostasis remain unclear. The study aimed to identify a regulatory branch of the mitochondrial unfolded protein response mediated by SIRT7 and NRF1 that links energy metabolism to stem cell proliferation. The authors mapped a UPR(mt) pathway in which SIRT7 and NRF1 interact to regulate mitochondrial protein folding stress and cellular energy metabolism, thereby influencing HSC proliferation. Loss of SIRT7 reduces HSC quiescence, elevates mitochondrial protein folding stress, and impairs regeneration, while restoring SIRT7 in aged HSCs rescues their regenerative capacity, demonstrating that dysregulation of this UPR(mt)-mediated metabolic checkpoint drives HSC aging and is reversible.

Abstract

Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. How stem cells maintain metabolic homeostasis remains elusive. Here, we identified a regulatory branch of the mitochondrial unfolded protein response (UPR(mt)), which is mediated by the interplay of SIRT7 and NRF1 and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress (PFS(mt)), and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 up-regulation improved the regenerative capacity of aged HSCs. These findings define the deregulation of a UPR(mt)-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.