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1313 Nynrin Preserves Hematopoietic Stem Cell Function Via the Ppif-Mediated Mitochondrial Permeability Transition

Program: Oral and Poster Abstracts
Session: 501. Hematopoietic Stem and Progenitor Cells and Hematopoiesis: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Fundamental Science, Research, hematopoiesis, Biological Processes
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Chengfang Zhou1*, Mei Kuang2*, Jianming Wang3*, Yu Luo3* and Yu Hou, PhD4

1institute of life sciences, Chongqing Medical University, Chongqing, China
2Department of Hematology, Army Medical University, Chongqing, China
3Institute of life sciences, Chongqing Medical University, Chongqing, China
4Institute of Life Sciences, Chongqing Medical University, CHONGQING, Chongqing, China

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.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH