Mitochondrial uncouplers impair human sperm motility without altering ATP content

Abstract

Sperm motility is necessary for successful fertilization, but there remains controversy about whether human sperm motility is primarily powered by glycolysis or oxidative phosphorylation. To evaluate the plausibility of reducing human sperm mitochondrial ATP production as an avenue for contraceptive development, we treated human sperm with small-molecule mitochondrial uncouplers, which reduce mitochondrial membrane potential by inducing passive proton flow, and evaluated the effects on a variety of physiological processes that are critical for fertilization. We also sought to clarify the subcellular localization of Adenosine Nucleotide Translocator 4 (ANT4), a gamete-specific protein that has been suggested as a contraceptive target. We determined that ANT4 is mitochondrially localized, that induced mitochondrial uncoupling can be partially mediated by the ANT family, and that two uncouplers, Niclosamide Ethanolamine and BAM15, significantly decreased sperm progressive motility. However, these uncouplers did not reduce sperm ATP content or impair other physiological processes, implying that human sperm can rely on glycolysis for ATP production in the absence of functional mitochondria. Thus, since certain mitochondrial uncouplers impair motility through ATP-independent mechanisms, they could be useful ingredients in on-demand, vaginally-applied contraceptives. However, systemically delivered contraceptives that target sperm mitochondria to reduce their ATP production would need to be paired with sperm-specific glycolysis inhibitors.

Effects of substrate availability and mitochondrial disruption on oxidative metabolism and sperm motility in fertile dogs

“…and uncoupling proteins (UCP) which are highly conserved in mammals and regulate mitochondrial bioenergetics and ROS production in human sperm (Jastroch et al, 2010;Moraes et al, 2021;Skinner et al, 2023). As a result, modulation of proton leak is a therapeutic target for many aspects of age-related disease.…”

“…In our study, OLIGO treated sperm in LP media showed significantly higher oxygen consumption than untreated and OLIGO treated sperm in any media. Proton leak includes both basal and inducible components, the latter catalysed by adenine nucleotide translocase (ANT) and uncoupling proteins (UCP) which are highly conserved in mammals and regulate mitochondrial bioenergetics and ROS production in human sperm (Jastroch et al., 2010; Moraes et al., 2021; Skinner et al., 2023). As a result, modulation of proton leak is a therapeutic target for many aspects of age‐related disease.…”