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Na, K-ATPase α4: A Novel Regulator of Sperm Energetics
Numata, September
Numata, September
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Abstract
Male factor infertility is a common condition that affects ~7% of men worldwide and for which specific treatment options are very limited. Conversely, a safe, effective, and reversible male contraceptive continues to be a highly desired, unmet goal. Progress in the management of both male fertility and contraception has been hindered by our incomplete knowledge of sperm physiology. Sperm are highly specialized cells that are subjected to extreme environmental conditions as they journey to the oocyte. A series of ion transporters expressed in the plasma membrane are necessary for sperm to sense and respond to various environmental cues. One such example is the Na, K-ATPase alpha 4 isoform (NKAα4), which is responsible for the exchange of 3 Na+ and 2 K+ across the plasma membrane. Genetic deletion of NKAα4 in mice has severe consequences for male fertility, resulting in complete sterility of male, but not female mice. Sperm from NKAα4 knockout (NKAα4 KO) mice display substantial decreases in total, progressive, and hyperactive motility, all of which rely on ample amounts of adenosine triphosphate (ATP). Accordingly, ATP levels were measured in sperm from NKAα4 KO mice and found to be significantly lower than WT counterparts. This prompted the examination of the pathways responsible for generating ATP in sperm, glycolysis and mitochondrial oxidative phosphorylation. Sperm from NKAα4 KO mice exhibited significant reductions in both glycolytic and mitochondrial activity compared to WT sperm.Thus, the objective of this work was to investigate the potential link between NKAα4 activity and sperm energetics. Specifically, our aim was to define the role of NKAα4 in the regulation of glycolytic and mitochondrial activity, energy production, and sperm function. We found that in addition to the decreases in glycolytic activity, mitochondrial function, and ATP levels, sperm from NKAα4 KO mice also displayed a significant reduction in glucose uptake. The decrease in glucose uptake by NKAα4 KO sperm suggested the presence of a Na+-dependent glucose uptake mechanism in sperm. This led to the discovery that the Sodium Glucose Cotransporter Isoform 1 (SGLT-1) is expressed in mouse sperm and is dependent on the transmembrane Na+ gradient generated and maintained by NKAα4. The pharmacological and genetic targeting of SGLT-1 revealed the importance of this transporter for sperm glycolysis, energy production, motility, and fertility.While SGLT-1 inhibition/deletion impaired sperm function, the ablation of NKAα4 in mice resulted in more severe energetic defects, suggesting the presence of an additional mechanism by which NKAα4 could be regulating sperm metabolism. We discovered that sperm from NKAα4 KO mice exhibit depolarization of the mitochondrial membrane potential, reduced mitochondrial Ca+ levels, and an increase in reactive oxygen species, all of which indicate mitochondrial dysfunction. Altogether, we found that NKAα4, by maintaining the steep transmembrane Na+ gradient, drives SGLT-1-mediated glucose uptake and glycolytic activity in sperm. Moreover, NKAα4 contributes to mitochondrial ion homeostasis, membrane potential, oxygen consumption, and redox balance. Developing a better understanding of the basic mechanisms that regulate sperm energy production has major translational implications for the development of agents aimed at enhancing or blocking male fertility.
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2023-08-31
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University of Kansas
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1001682_1.pdf
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Keywords
Physiology, Cellular biology, Biology, capacitation, energetics, glycolysis, mitochondria, motility, sperm