Nynrin Preserves Hematopoietic Stem Cell Function Via the Ppif-Mediated Mitochondrial Permeability Transition

Mitochondria have recently been identified as a critical regulator for homeostasis of hematopoietic stem cells (HSCs). However, the mechanism underlying HSC regulation remains poorly clarified. Here, we identify transcription factor Nynrin as a novel regulator of HSC maintenance through modulation of mitochondrial function. We demonstrate that Nynrin knockout leads to significantly decreased long-term HSC frequency, markedly reduced HSC dormancy and self-renewal capacity in steady-state and stress hematopoiesis. Nynrin-deficient HSCs are more compromised in tolerance of irradiation- and 5-fluorouracil-induced stresses and exhibit typical phenotypes of necrosis. Mechanistically, Nynrin deletion induces transactivation of Ppif, its product cyclophilin D is one of the prominent members of mitochondrial permeability transition (mPT). Overexpression of Ppif exhausts long-term HSC, impairs genotoxic hematopoietic recovery, and enhances mPT, resulting in mitochondrial swelling and reactive oxygen species production. Suppression of Ppif essentially rescues the phenotypic and functional defects in Nynrin-deleted HSCs. Collectively, our data, for the first time, characterize Nynrin as a critical regulator of HSC function acting through the Ppif/ mPT mitochondria axis and highlight the importance of Nynrin in HSC maintenance. These observations provide new insights into the mechanisms for controlling HSC fate.