Mitochondrial uncouplers impair human sperm motility without altering ATP content†

Area of Science:

• Reproductive Biology
• Sperm Physiology
• Membrane Biophysics

Background:

• Electrochemical potentials across sperm mitochondrial and plasma membranes influence functionality.
• Targeting sperm mitochondria is a potential contraceptive strategy, but its efficacy needs validation.
• The precise roles of mitochondrial and plasma membrane potentials in sperm fertility remain unclear.

Purpose of the Study:

• To determine if mitochondrial and plasma membrane potentials are essential for human sperm fertility.
• To evaluate the effects of mitochondrial uncouplers on sperm physiology.
• To explore potential contraceptive applications based on these findings.

Main Methods:

• Human sperm were treated with mitochondrial uncouplers (niclosamide ethanolamine and BAM15).
• Effects on sperm motility, adenosine triphosphate (ATP) levels, and other physiological processes were assessed.
• The specific actions of each uncoupler on mitochondrial and plasma membranes were investigated.

Main Results:

• Both BAM15 and niclosamide ethanolamine reduced sperm progressive motility, with niclosamide ethanolamine showing a stronger effect.
• Mitochondrial uncouplers did not deplete sperm ATP levels, indicating reliance on glycolysis.
• Niclosamide ethanolamine impaired motility via an ATP-independent pathway.

Conclusions:

• Human sperm can utilize glycolysis for ATP production even when mitochondria are impaired.
• Systemic contraceptives targeting sperm mitochondria may require co-administration with glycolysis inhibitors.
• Niclosamide ethanolamine's unique mechanism and safety profile suggest potential for topical, on-demand contraceptives.