Sperm mitochondrial uncoupling

Mitochondrial Uncoupling Diagram

Mitochondria generate ATP by coupling the activities of two large transport protein complexes on the inner mitochondrial membrane (IMM) – the Electron Transport Chain (ETC) and ATP Synthase. The ETC pumps Hydrogen ions (H+) out of the mitochondrial matrix to generate an electrochemical H+ gradient (ΔΨ) across the IMM. ATP Synthase then allows H+ to diffuse back into the mitochondrial matrix and, like a molecular water wheel, uses the energy released by this diffusion to synthesize ATP.

It was originally assumed that H+ ions could only return to the matrix through ATP synthase, but it is now well-established that there are other proteins in the IMM which can allow H+ to return to the mitochondrial matrix, but do not generate ATP and instead dissipate the released energy as heat. This phenomenon, known as mitochondrial uncoupling, is crucial for mitochondrial function and integrity.  In the specialized thermogenic tissues, brown and beige fat, mitochondrial uncoupling helps to maintain core body temperature and control body weight, and is mediated by uncoupling protein 1 (UCP1).

In most other tissues, mitochondria are more rarely uncoupled, and when they are uncoupled, they carry a smaller H+ current across the IMM.  However, because this “mild” uncoupling occurs in the majority of tissues, it may have a significant impact on thermogenesis, body weight, healthy metabolism and reproduction potential.

Recently, it was demonstrated that mild mitochondrial uncoupling is mediated by Adenosine Nucleotide Transporter (ANT) proteins. These proteins’ primary function is to transport ATP out of the mitochondrial matrix, but when activated by chemical uncouplers, they also allow H+ ions to pass through, thereby uncoupling the mitochondria – reducing the IMM potential and slowing  the synthesis of ATP. In humans and mice, there are several ANT isoforms, and human ANT4 is exclusively expressed in sperm.

ANT4 has been previously recognized as an excellent contraceptive target, and we aim to activate its uncoupling function, thereby draining sperm of energy and making them unable to find and fertilize an egg. This approach may lead to the creation of unisex contraceptives with fewer side effects than were found in previous attempts to target ANT4.