TY - JOUR
T1 - Adult stem cell deficits drive Slc29a3 disorders in mice
AU - Nair, Sreenath
AU - Strohecker, Anne M.
AU - Persaud, Avinash K.
AU - Bissa, Bhawana
AU - Muruganandan, Shanmugam
AU - McElroy, Craig
AU - Pathak, Rakesh
AU - Williams, Michelle
AU - Raj, Radhika
AU - Kaddoumi, Amal
AU - Sparreboom, Alex
AU - Beedle, Aaron M.
AU - Govindarajan, Rajgopal
N1 - Publisher Copyright:
© 2019, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Mutations exclusively in equilibrative nucleoside transporter 3 (ENT3), the only intracellular nucleoside transporter within the solute carrier 29 (SLC29) gene family, cause an expanding spectrum of human genetic disorders (e.g., H syndrome, PHID syndrome, and SHML/RDD syndrome). Here, we identify adult stem cell deficits that drive ENT3-related abnormalities in mice. ENT3 deficiency alters hematopoietic and mesenchymal stem cell fates; the former leads to stem cell exhaustion, and the latter leads to breaches of mesodermal tissue integrity. The molecular pathogenesis stems from the loss of lysosomal adenosine transport, which impedes autophagy-regulated stem cell differentiation programs via misregulation of the AMPK-mTOR-ULK axis. Furthermore, mass spectrometry-based metabolomics and bioenergetics studies identify defects in fatty acid utilization, and alterations in mitochondrial bioenergetics can additionally propel stem cell deficits. Genetic, pharmacologic and stem cell interventions ameliorate ENT3-disease pathologies and extend the lifespan of ENT3-deficient mice. These findings delineate a primary pathogenic basis for the development of ENT3 spectrum disorders and offer critical mechanistic insights into treating human ENT3-related disorders.
AB - Mutations exclusively in equilibrative nucleoside transporter 3 (ENT3), the only intracellular nucleoside transporter within the solute carrier 29 (SLC29) gene family, cause an expanding spectrum of human genetic disorders (e.g., H syndrome, PHID syndrome, and SHML/RDD syndrome). Here, we identify adult stem cell deficits that drive ENT3-related abnormalities in mice. ENT3 deficiency alters hematopoietic and mesenchymal stem cell fates; the former leads to stem cell exhaustion, and the latter leads to breaches of mesodermal tissue integrity. The molecular pathogenesis stems from the loss of lysosomal adenosine transport, which impedes autophagy-regulated stem cell differentiation programs via misregulation of the AMPK-mTOR-ULK axis. Furthermore, mass spectrometry-based metabolomics and bioenergetics studies identify defects in fatty acid utilization, and alterations in mitochondrial bioenergetics can additionally propel stem cell deficits. Genetic, pharmacologic and stem cell interventions ameliorate ENT3-disease pathologies and extend the lifespan of ENT3-deficient mice. These findings delineate a primary pathogenic basis for the development of ENT3 spectrum disorders and offer critical mechanistic insights into treating human ENT3-related disorders.
UR - https://www.scopus.com/pages/publications/85068380559
UR - https://www.scopus.com/pages/publications/85068380559#tab=citedBy
U2 - 10.1038/s41467-019-10925-3
DO - 10.1038/s41467-019-10925-3
M3 - Article
C2 - 31270333
AN - SCOPUS:85068380559
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2943
ER -
