Unravelling the mystery of PXo bodies: Insights into a newly identified cell organelle

The Drosophila melanogaster, commonly known as the fruit fly and one of the most extensively studied species in the animal kingdom, recently brought to our attention a possible new cell organelle called “PXo bodies” in a study conducted by Xu et al. ¹ The research team noticed that chronic phosphate deprivation, a crucial nutrient involved in the synthesis of ATP and the cell membrane, led to hyperproliferation of the midgut epithelium. ¹ Observations revealed that chronic Pi (inorganic phosphate) starvation, caused by feeding flies PFA or chemically defined food low in phosphate, led to the down-regulation of a protein called PXo, a novel transporter of inorganic phosphate. Controlled experiments then showed that PXo deficiency also resulted in gut hyperproliferation, bringing forth the conclusion that PXo was playing a certain role in these ultimate pathogenic changes of a decreased Pi. During the process of analyzing and understanding the mechanisms and interactions at play, labeled PXo was seen to be transporting Pi to a multilaminar, spiraled, membranous cell body under the electron microscope. ¹ Unsuccessful staining in an effort to categorize these structures into a subtype or possible variant of a preexisting organelle brought forth the hypothesis that they perhaps had stumbled upon a new organelle, which was ultimately named PXo bodies in honor of their association with the protein.

Of all the structures in the cell, the PXo bodies appear to bear resemblance with lamellar bodies, Golgi bodies, and endosomes; however, the closest relationship is with Golgi bodies. Not only were PXo bodies found in close proximity to them, but the lockdown of yCOP, which causes inhibition of protein transport from Golgi bodies, resulted in fragmentation and decline in the number of PXo bodies, suggesting their necessity for PXo body synthesis, propagation or both. ¹ However, they remain distinct from Golgi bodies and other organelles, as showcased by their absence of distinguishing biomarkers carried by the other cell organelles.

As initially stated, the discovery of this organelle occurred while studying the response of enteric cells of the fruit fly in a Pi-deficient environment, and alongside the findings discussed above, it was also noticed that there was an increase in PXo body breakdown ¹ : releasing phosphate into the cytosol. Considering the hyperproliferation of enteric cells that is taking place, this release of phosphate would be beneficial as Pi is essential in the formation and functioning of the cell; however, the catch lies in the fact that the proliferation is occurring in conditions of low phosphate levels; which all in all seems contradictory. Why would an organism store and produce more cells in times of deficiency of a required nutrient, and why would it break down its stores instead of choosing to store more phosphate? This brings us back to PXo and its role in mediating the events of this particularly confusing cascade. Studies have shown that a deficiency of PXo (caused by a shortage of Pi) can activate progenitor cells, leading to their multiplication and differentiation into enteric cells (Figure 1). This process is triggered by a stress response that removes the antagonistic blockade on Cka. Once activated, Cka initiates the changes we observe. Thus, if presuming that PXo downregulation somewhat simultaneously triggers both hypercellularity and PXo body breakdown, the requirement of phosphate release does seem understandable, and as the author also states, the increased cellularity may, in turn, allow an improved efficiency of utilization and uptake of the now highly available Pi. ¹ However, there is still the possibility that the Cka-mediated progenitor proliferation is not entirely dependent on Pi, as many other factors can also induce Cka activation. Despite this, the association of PXo with Cka is well backed up by Xu et al., opening a large number of possibilities regarding what chain of events this novel interplay can produce. Another question that naturally arises with the proliferation of enteric cells is whether PXo and PXo bodies are only specific to the midgut. Data states a strong association of PXo with enteroendocrine cells, ² the topic of which is relatively untouched and holds quite a potential in defining the role of PXo bodies.

Figure 1.

Diagram showing PXo bodies and connections between Pi storage, PXo, and Pi signaling.

The animal kingdom boasts a myriad of organisms, each having evolved to meet their specific needs, making it entirely possible that phosphate storage, release, and regulation may also have evolved in relation to the needs of the animal of interest. For example, PolyP bodies, which are linear chains of inorganic phosphates linked together by high energy bonds, are perhaps orthologous to PXo bodies whose presence and use have been studied to various degrees amongst various cells. In relation to human beings, PolyP bodies play a role that is almost as crucial as phosphate itself. They provide a source of phosphate for bone mineralization, induce gene expression that leads to cell differentiation, and act as an energy store and donor in extracellular spaces. ³ This brings us to question the extent of the importance of PXo bodies in other animals and whether they and their role transcend into higher organisms.

Though described as a ‘new’ organelle, they are perhaps better worded as a ‘newly described’ organelle. It does seem implausible that such large, abnormally staining organelles went unnoticed all these years. However, as the researchers point out, PXo body-like structures can be seen in the electron microscopy imaging of fly midgut cells in other studies too. ⁴ This now triggers not only a search for similar cell bodies in other animals but also a retrospective look back into the studies on D. Melanogaster so far. This deep dive is necessary to better understand whether PXo bodies are the result of evolution, vestigial organelles from evolved eukaryotic cells, or if they have been simply overlooked all this time. It is, however, undisputed that Xu et al. have provided an intensive collection of information, with doors still open for defining these bodies with precision.