TY - JOUR
T1 - Redox regulation by TXNRD3 during epididymal maturation underlies capacitation-associated mitochondrial activity and sperm motility in mice
AU - Wang, Huafeng
AU - Dou, Qianhui
AU - Jeong, Kyung Jo
AU - Choi, Jungmin
AU - Gladyshev, Vadim N.
AU - Chung, Jean Ju
N1 - Funding Information:
We thank the Harvard Medical School EM facility (TEM) and the Yale Center for Cellular and Molecular Imaging (SEM) for assistance in electron microscopy, Jae Yeon Hwang for help in analyzing TEM images of sperm mitochondria, and Xiaofang Huang for initial analysis of free thiol measurement. J.-J. C. and V. N. G. conceptualization; J.-J. C. and V. N. G. supervision; J.-J. C. and H. W. methodology; H. W. Q. D. and J.-J. C. investigation; H. W. K. J. J. and J. C. formal analysis; H. W. visualization; H. W. and J.-J. C. writing-original draft; H. W. V. N. G. and J.-J. C. writing-review and editing; J.-J. C. and H. W. validation; J. C. V. N. G. and J.-J. C. resources; V. N. G. and J.-J. C. project administration; V. N. G. and J.-J. C. funding acquisition. This work was funded by NIH R01GM065204 to V. N. G. and the start-up funds from Yale School of Medicine and NIH R01HD096745 to J.-J. C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2022 The Authors
PY - 2022/7
Y1 - 2022/7
N2 - During epididymal transit, redox remodeling protects mammalian spermatozoa, preparing them for survival in the subsequent journey to fertilization. However, molecular mechanisms of redox regulation in sperm development and maturation remain largely elusive. In this study, we report that thioredoxin-glutathione reductase (TXNRD3), a thioredoxin reductase family member particularly abundant in elongating spermatids at the site of mitochondrial sheath formation, regulates redox homeostasis to support male fertility. Using Txnrd3−/− mice, our biochemical, ultrastructural, and live cell imaging analyses revealed impairments in sperm morphology and motility under conditions of TXNRD3 deficiency. We find that mitochondria develop more defined cristae during capacitation in wildtype sperm. Furthermore, we show that absence of TXNRD3 alters thiol redox status in both the head and tail during sperm maturation and capacitation, resulting in defective mitochondrial ultrastructure and activity under capacitating conditions. These findings provide insights into molecular mechanisms of redox homeostasis and bioenergetics during sperm maturation, capacitation, and fertilization.
AB - During epididymal transit, redox remodeling protects mammalian spermatozoa, preparing them for survival in the subsequent journey to fertilization. However, molecular mechanisms of redox regulation in sperm development and maturation remain largely elusive. In this study, we report that thioredoxin-glutathione reductase (TXNRD3), a thioredoxin reductase family member particularly abundant in elongating spermatids at the site of mitochondrial sheath formation, regulates redox homeostasis to support male fertility. Using Txnrd3−/− mice, our biochemical, ultrastructural, and live cell imaging analyses revealed impairments in sperm morphology and motility under conditions of TXNRD3 deficiency. We find that mitochondria develop more defined cristae during capacitation in wildtype sperm. Furthermore, we show that absence of TXNRD3 alters thiol redox status in both the head and tail during sperm maturation and capacitation, resulting in defective mitochondrial ultrastructure and activity under capacitating conditions. These findings provide insights into molecular mechanisms of redox homeostasis and bioenergetics during sperm maturation, capacitation, and fertilization.
KW - TXNRD3
KW - male fertility
KW - mitochondrial function
KW - redox homeostasis
KW - thioredoxin glutathione reductase
KW - ultrastructure
UR - http://www.scopus.com/inward/record.url?scp=85132241978&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2022.102077
DO - 10.1016/j.jbc.2022.102077
M3 - Article
C2 - 35643315
AN - SCOPUS:85132241978
SN - 0021-9258
VL - 298
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
M1 - 102077
ER -