Adult stem cell deficits drive Slc29a3 disorders in mice

Sreenath Nair, Anne M. Strohecker, Avinash K. Persaud, Bhawana Bissa, Shanmugam Muruganandan, Craig McElroy, Rakesh Pathak, Michelle Williams, Radhika Raj, Amal Kaddoumi, Alex Sparreboom, Aaron M. Beedle and Rajgopal Govindarajan ()
Additional contact information
Sreenath Nair: Ohio State University
Anne M. Strohecker: Ohio State University
Avinash K. Persaud: Ohio State University
Bhawana Bissa: Ohio State University
Shanmugam Muruganandan: Ohio State University
Craig McElroy: Ohio State University
Rakesh Pathak: Ohio State University
Michelle Williams: Ohio State University
Radhika Raj: Ohio State University
Amal Kaddoumi: Auburn University
Alex Sparreboom: Ohio State University
Aaron M. Beedle: SUNY Binghamton University
Rajgopal Govindarajan: Ohio State University

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10925-3

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