Michigan State University scientists have pinpointed the molecular “switch” that supercharges sperm for their final sprint to an egg — a breakthrough that could reshape infertility treatments and pave the way for safe, nonhormonal male contraceptives.
“Sperm metabolism is special since it’s only focused on generating more energy to achieve a single goal: fertilization,” said Melanie Balbach, an assistant professor in the Department of Biochemistry and Molecular Biology and senior author of the paper.
Before ejaculation, mammalian sperm rest in a low-energy state. Afterward, as they swim through the female reproductive tract, they undergo a series of changes that ultimately help them reach and fertilize an egg. These include swimming with quick, vigorous movements, as well as a change to the membranes that will encounter an egg.
“Many types of cells undergo this rapid switch from low to high energy states, and sperm are an ideal way to study such metabolic reprogramming,” said Balbach, who, in 2023, brought her pioneering science on sperm metabolism to MSU.
As a postdoctoral researcher at Weill Cornell Medicine, Balbach drove the headline-making discovery that the inhibition of a crucial sperm enzyme rendered mice temporarily infertile. This breakthrough raised the exciting potential for a nonhormonal male birth control.
Metabolism is similarly essential for sperm function, and while scientists knew that behavioral changes prior to fertilization required a large amount of energy, they weren’t sure how sperm adjusted to meet the demand — until now.
Teaming up with scientists at Memorial Sloan Kettering Cancer Center and the Van Andel Institute, Balbach’s group created a special technique that allowed them to track the metabolism of glucose, which sperm take up from their environment and use as a sort of fuel.
By tracing the chemical journey of glucose within sperm, they observed key differences between dormant and active specimens.
“You can think of this approach like painting the roof of a car bright pink and then following that car through traffic using a drone,” Balbach explained.
“In activated sperm, we saw this painted car moving much faster through traffic while preferring a distinct route and could even see what intersections the car tended to get stuck at,” she added.
By leveraging facilities such as MSU’s Mass Spectrometry and Metabolomics Core, the study paints a fuller picture of the high-energy, multistep process required for sperm to reach their goal of fertilization.
This includes the discovery that a particular enzyme called aldolase helps sperm convert glucose into energy and that sperm even utilize molecular fuel that they already have on board when they begin their trek.
The experiments also revealed how some enzymes regulate the flow of glucose like traffic controllers.
Looking ahead, Balbach will continue to explore how sperm use a variety of fuel sources like glucose and fructose to meet their energy needs. This research can potentially impact a number of reproductive health issues.
With one in six individuals impacted by infertility globally, Balbach sees the analysis of sperm metabolism as an especially promising research direction for improving both assisted fertility techniques and the diagnosis of infertility in patients.
This work can also help develop new methods of contraception like nonhormonal birth control.
“Better understanding the metabolism of glucose during sperm activation was an important first step, and now we’re aiming to understand how our findings translate to other species, like human sperm,” Balbach said.
“One option is to explore if one of our ‘traffic-control’ enzymes could be safely targeted as a nonhormonal male or female contraceptive,” she added.
The traditional development of male contraceptives has focused on blocking sperm at their creation. This approach, however, comes with notable drawbacks. The process of becoming infertile is far from on demand, and such contraceptives are commonly hormone-based, leading to many severe side effects.
The latest findings from Balbach and her collaborators are paving the way for a sperm metabolism-centered solution to these challenges: an inhibitor-based, nonhormonal method of contraception that would allow for on-demand male infertility with little to no side effects.
“Right now, about 50% of all pregnancies are unplanned, and this would give men additional options and agency in their fertility,” Balbach said. “Likewise, it creates freedom for those using female birth control, which is hormone-based and highly prone to side effects.
“I’m excited to see what else we can find and how we can apply these discoveries.”
Appearing in the Proceedings of the National Academy of Sciences, the Michigan State University-led project was supported by funding from the National Institute of Child Health and Human Development.
