Spermatogonial Gene Networks Selectively Couple to Glutathione and Pentose Phosphate Metabolism but Not Cysteine Biosynthesis

David Prokai; Ashutosh Pudasaini; Mohammed Kanchwala; Andrew T. Moehlman; Alexandrea E. Waits; Karen M. Chapman; Jaideep Chaudhary; Jesus Acevedo; Patrick Keller; Xing Chao; Bruce R. Carr; F. Kent Hamra

iScience (Jan 2021)

Spermatogonial Gene Networks Selectively Couple to Glutathione and Pentose Phosphate Metabolism but Not Cysteine Biosynthesis

David Prokai,
Ashutosh Pudasaini,
Mohammed Kanchwala,
Andrew T. Moehlman,
Alexandrea E. Waits,
Karen M. Chapman,
Jaideep Chaudhary,
Jesus Acevedo,
Patrick Keller,
Xing Chao,
Bruce R. Carr,
F. Kent Hamra

Affiliations

David Prokai: Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ashutosh Pudasaini: Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; GenomeDesigns Laboratory, LLC, 314 Stonebridge Drive, Richardson, TX 75080, USA
Mohammed Kanchwala: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Andrew T. Moehlman: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Alexandrea E. Waits: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Karen M. Chapman: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jaideep Chaudhary: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jesus Acevedo: Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Cecil H. & Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Patrick Keller: Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Cecil H. & Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Xing Chao: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Bruce R. Carr: Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
F. Kent Hamra: Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Cecil H. & Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author

Journal volume & issue: Vol. 24, no. 1
p. 101880

Abstract

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Summary: In adult males, spermatogonia maintain lifelong spermatozoa production for oocyte fertilization. To understand spermatogonial metabolism we compared gene profiles in rat spermatogonia to publicly available mouse, monkey, and human spermatogonial gene profiles. Interestingly, rat spermatogonia expressed metabolic control factors Foxa1, Foxa2, and Foxa3. Germline Foxa2 was enriched in Gfra1Hi and Gfra1Low undifferentiated A-single spermatogonia. Foxa2-bound loci in spermatogonial chromatin were overrepresented by conserved stemness genes (Dusp6, Gfra1, Etv5, Rest, Nanos2, Foxp1) that intersect bioinformatically with conserved glutathione/pentose phosphate metabolism genes (Tkt, Gss, Gclc, Gclm, Gpx1, Gpx4, Fth), marking elevated spermatogonial GSH:GSSG. Cystine-uptake and intracellular conversion to cysteine typically couple glutathione biosynthesis to pentose phosphate metabolism. Rat spermatogonia, curiously, displayed poor germline stem cell viability in cystine-containing media, and, like primate spermatogonia, exhibited reduced transsulfuration pathway markers. Exogenous cysteine, cysteine-like mercaptans, somatic testis cells, and ferroptosis inhibitors counteracted the cysteine-starvation-induced spermatogonial death and stimulated spermatogonial growth factor activity in vitro.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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