Researchers Uncover Novel Mechanism for De Novo Polarity Establishment (Biology)

Sperm from males must be activated or capacitated on the right time and right place in order to achieve fertilization success. Sperm activation is a process whereby round and still spermatids differentiate into asymmetric and motile spermatozoa without the transcriptional and translational modification. The molecular mechanism underlying this de novo symmetry-breaking process, however, remains largely unknown.

C. elegans sperm contain relatively few organelles, namely a haploid nucleus, mitochondria, and membranous organelles (MOs). In the late stage of sperm activation, the MO membrane fuses with the plasma membrane (PM), leaving a permanent invagination on the cell body surface.

In a study published online in Developmental Cell, Dr. MIAO Long’s team at the Institute of Biophysics of the Chinese Academy of Sciences revealed that during nematode C. elegans sperm activation, Na+/K+-ATPase (also known as Na+/K+ pump), which is initially present on the PM, moves centripetally toward cell body and subsequently enters the fusion pore in the cell body, and the polarization of Na+/K+ pump depends on the transport of cholesterol from the PM to intracellular MOs via membrane contact sites (MCSs).

The researchers found that MOs are apposed at approximately 10 nm to the PM, which indicates that MOs may form MCSs with the PM. There is increasing evidence that MCSs are formed by tether proteins between tightly apposed membranes of diverse organelles, including the PM. The MCSs provide an efficient platform for lipid and ion transfer between distinct organelles in a non-vesicular manner.

Besides, they revealed that in C. elegans sperm, cholesterol is evenly distributed on the PM and is highly enriched in MOs. During sperm activation, Na+/K+ pump and cholesterol transport on the PM is correlated. Both Na+/K+ pump and cholesterol are similarly sorted and transported against their concentration gradients. Cholesterol moves from the PM to MOs against its concentration gradient through the MCSs stably formed between MOs and the PM.

The association between the PI4P phosphatase SAC-1 and MOs implies that the localized PI4P hydrolysis on the PM catalyzed in trans by SAC-1 may provide the energy required for transporting cholesterol from the PM to MOs. A phosphoinositide 5-phosphatase, CIL-1, which preferentially converts PI(4,5)P2 to PI4P, may regulate PI4P biosynthesis, which in turn maintains the driving force to modulate cholesterol trafficking and Na+/K+ pump translocation during sperm activation.

This study implies that lipid transfer at MCSs might facilitate the translocation of ion channels and transporters to modulate cell polarity establishment and cell motility acquisition. Further studies on MOs in C. elegans sperm, for example, investigations on their molecular compositions and formation mechanism, will help to elucidate the functions of lipid homeostasis and lipid transfer proteins in regulating membrane dynamics and organelle interactions in other cell types.

Featured image: Graphical abstract by authors

Reference: Qiushi Wang et al., “Membrane contact site-dependent cholesterol transport regulates Na+/K+-ATPase polarization and spermiogenesis in Caenorhabditis elegans”, Developmental Cell, 2021. DOI:

Provided by Chinese Academy of Sciences

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