Mitochondrial Calcium Uptake Promotes Mitochondrial Activation and Hyperactivated Motility During Human Sperm Capacitation
- 1Department of Obstetrics and Gynecology, Center for Reproductive Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United S
Abstract
Capacitation is a post-ejaculatory maturation process by which sperm become hyperactive and undergo the acrosome reaction, both of which are required to fertilize an oocyte. Two key features of capacitation are increased intracellular calcium via the calcium channel CatSper and changes in mitochondrial function. In mouse spermatozoa, CatSper-dependent calcium entry promotes mitochondrial calcium uptake and mitochondrial activation, contributing to hyperactivated motility and fertilization ability. Whether this mechanism is conserved in human spermatozoa was unknown. Here, we assessed mitochondrial function and mitochondrial calcium in paired non-capacitated and capacitated human spermatozoa from normozoospermic donors. Capacitation increased mitochondrial respiratory control ratio, coupling efficiency, mitochondrial membrane potential, and mitochondrial calcium. The increase in mitochondrial calcium required extracellular calcium and was prevented by pharmacological inhibition of CatSper or the mitochondrial calcium uniporter (MCU). Inhibition of CatSper or mitochondrial calcium uniporter also attenuated the capacitation-associated increase in mitochondrial membrane potential and reduced hyperactivated motility without affecting progressive or total motility. Pharmacological disruption of mitochondrial function reduced capacitation-associated hyperactivated motility without affecting the acrosome reaction. Together, these findings support a conserved pathway in human and mouse spermatozoa in which CatSper-mediated calcium entry promotes MCU-dependent mitochondrial calcium uptake and mitochondrial activation, contributing to the acquisition of hyperactivated motility during capacitation. These findings identify mitochondrial calcium handling as a potential target for modulating human spermatozoa function.
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BibTeX
@misc{irigoyen2026mitochondrial,
title = {{Mitochondrial Calcium Uptake Promotes Mitochondrial Activation and Hyperactivated Motility During Human Sperm Capacitation}},
author = {P. Irigoyen and J. J. Ferreira and A. Cassina and S. M. Bhagwat and N. Peramsetty and R. Sapiro and C. M. Santi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755036},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755036v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mitochondrial Calcium Uptake Promotes Mitochondrial Activation and Hyperactivated Motility During Human Sperm Capacitation
AU - P. Irigoyen
AU - J. J. Ferreira
AU - A. Cassina
AU - S. M. Bhagwat
AU - N. Peramsetty
AU - R. Sapiro
AU - C. M. Santi
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755036
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755036v1
AB - Capacitation is a post-ejaculatory maturation process by which sperm become hyperactive and undergo the acrosome reaction, both of which are required to fertilize an oocyte. Two key features of capacitation are increased intracellular calcium via the calcium channel CatSper and changes in mitochondrial function. In mouse spermatozoa, CatSper-dependent calcium entry promotes mitochondrial calcium uptake and mitochondrial activation, contributing to hyperactivated motility and fertilization ability. Whether this mechanism is conserved in human spermatozoa was unknown. Here, we assessed mitochondrial function and mitochondrial calcium in paired non-capacitated and capacitated human spermatozoa from normozoospermic donors. Capacitation increased mitochondrial respiratory control ratio, coupling efficiency, mitochondrial membrane potential, and mitochondrial calcium. The increase in mitochondrial calcium required extracellular calcium and was prevented by pharmacological inhibition of CatSper or the mitochondrial calcium uniporter (MCU). Inhibition of CatSper or mitochondrial calcium uniporter also attenuated the capacitation-associated increase in mitochondrial membrane potential and reduced hyperactivated motility without affecting progressive or total motility. Pharmacological disruption of mitochondrial function reduced capacitation-associated hyperactivated motility without affecting the acrosome reaction. Together, these findings support a conserved pathway in human and mouse spermatozoa in which CatSper-mediated calcium entry promotes MCU-dependent mitochondrial calcium uptake and mitochondrial activation, contributing to the acquisition of hyperactivated motility during capacitation. These findings identify mitochondrial calcium handling as a potential target for modulating human spermatozoa function.
ER -