By Efrat Ohayon
On June 25, 2025, the University of Virginia made an announcement that could lead to groundbreaking advancements in genetic diseases treatment. A new organelle inside mammalian cells called the hemifusome had been discovered. For 85 years, the model of human cells has remained the same. The discovery of a new organelle means that our understanding of cellular pathways may need to change, and this could lead to the discovery of new cures for diseases.
Scientists from UVA and the National Institutes of Health (NIH) suspect that the hemifusome’s main role is cell communication and transportation. This helps narrow down the diseases that may benefit from this discovery. Hermansky-Pudlak syndrome, for example, is caused by malfunctions in cellular transport.With the discovery of the hemifusome, and the understanding that one of its known functions is in the transportation of material within the cell, this organelle may be relevant in discovering a new treatment. The identification of the hemifusome, which plays a role in the transportation of material within the cell, presents a new way to look at and possibly cure diseases like this one.
In order to understand how the discovery of the hemifusome can lead to these advancements, it is important to understand what exactly this organelle is. The hemifusome is made up of heterotypic vesicle pairs that are partially bonded together by the hemifusome diaphragm, a membrane that was initially overlooked by scientists due to these configurations being thought to be too unstable to last within the cell membrane. The two vesicles that make up the hemifusome are slightly different. While the larger one has granular material, the smaller one is translucent. The existence of these two vesicles is significant because it provides evidence to the active transformation process of the hemifusome. Scientists believe hemifusomes undergo a process of reverse fusion, where the hemifusomes begin with the smaller vesicle outside of the larger one before flipping inward. This connection between the two vesicles eventually narrows to a thin stalk that breaks off, creating a free internal vesicle within the larger vesicle. This dynamic process represents a newly discovered mechanism for forming the internal vesicles that make up multivesicular bodies.
Additionally, the hemifusome diaphragm, which connects the two vesicles, measures approximately 158 nanometers, which is 10 times larger than the 10-nanometer diaphragms that are typically found when membranes merge. This size suggests that hemifusomes are stable organelles rather than temporary structures that assemble and disassemble based on the needs of the cell.
One reason the discovery of the hemifusome was delayed was because of previous microscopy method limitations. While most organelles of the cell were discovered using the transmission electron microscope, cryo-electron microscopy was necessary for the discovery of the hemifusome. The use of cryo-electron tomography allowed scientists to flash freeze the cell, leading to the visualization of processes that previously were unable to be captured due to their temporary presence in the cell, as the process of vesicle formation occurred too quickly to be seen. With these advancements, it was determined that hemifusomes make up around ten percent of vesicular organelles, demonstrating this organelle’s importance in cellular functions.
Previously, it was believed that most multivesicular bodies (MVBs), which function in processes such as cell communication, immune functions and preventing neurological diseases, had been formed through a protein-based process called the ESCRT (endosomal sorting complexes required for transport) pathway. This process is characterized by the alteration of the cell membrane through scission, which is crucial for cell division, and protein degradation. This pathway results in an internal vesicle, as the formation starts forming from the inside. The hemifusome, on the other hand, starts on the outside of the vesicle with the presence of the hemifusion diaphragm. This diaphragm separates the cytoplasm from the interior of the vesicle. The presence of the external hemifusion diaphragm differentiates hemifusome-based vesicle formation from ESCRT-based budding, making it unique.
The hemifusome seems to rely on lipid-based remodeling, rearranging membrane fats rather than utilizing proteins. This is significant as it represents a different pathway for the formation of vesicles which had not been previously discovered, providing a new understanding for how cells process materials. Furthermore, this alternate pathway could assist scientists in understanding genetic disorders where the ESCRT pathway is non-functional. For example, Hermansky-Pudlak syndrome is caused by malfunctions in cellular transport. With the discovery of the hemifusome, and the understanding that one of its known functions is in the transportation of material within the cell, this organelle may be relevant in discovering a new treatment. The discovery of the hemifusome could lead to targeted therapies in diseases that affect cellular pathways
Still, many questions remain unanswered. Scientists need to determine how hemifusomes function in healthy versus diseased cells, what molecular signals trigger their formation and if they are only found at the periphery of the cell. As the University of Virginia’s Dr. Seham Ebrahim said, “Finding something truly new inside cells is rare and it gives us a whole new path to explore.” This discovery reminds us that while we have uncovered much about cells, there is still a lot that is unknown. Understanding the hemifusome pathway is promising, as it may lead to targeted therapies for genetic disorders.
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