Pi plays crucial metabolic and structural roles in living organisms. It is essential for bioenergetics (ATP, GTP), metabolic regulation through glycolysis and oxidative phosphorylation, intercellular signaling pathways, cell proliferation (as part of DNA and RNA), and formation of bones and membranes. Consequently, the intracellular concentration and total body content of Pi are tightly regulated, and the maintenance of cellular Pi homeostasis is essential. Transporters that facilitate Pi translocation across cellular membranes are integral to this regulation. In humans, there are two protein families of sodium (Na+)-dependent Pi importers, SLC20 and SLC34. A sole Pi exporter has been identified – SLC53A1. The mitochondrial carrier SLC25A2 transports Pi across the mitochondrial inner membrane to support ATP synthesis. Other transporter families, such as SLC37, are also implicated in Pi flux, although knowledge of their cellular functions and substrate profiles is incomplete. Highlighting critical roles in human physiology, Pi transporter dysfunction leads to hypo- and hyperphosphatemia that are associated with cancer, mitochondrial energy impairment, metabolic diseases, and calcific diseases of numerous tissues, including the lung and brain. There are several notable opportunities for therapeutic intervention. Loss-of-function mutations in the SLC20A2 and SLC53A1 genes lead to brain calcifications. These abnormal calcium phosphate deposits are common in individuals with neurological, metabolic, or developmental disorders, and otherwise normal older adults, and cause a range of neurological symptoms, including migraines, Parkinsonism, psychosis, and dementia. Additionally, in ovarian and uterine cancers, overexpression of the SLC34A2 importer is a hallmark of disease, allowing it to serve as a biomarker. Furthermore, it has been shown that preventing export of Pi through SLC53A1 from these cancer cells leads to Pi toxicity and cell death. SLC53A1 inhibitors are being explored as potential therapeutics.

Previous investigations into Pi transporter families have relied almost exclusively on animal physiology and cellular assays to infer protein function and mechanism. By exploiting structural approaches, we are exploring questions concerning mechanisms of ion transport, their cellular regulation, as well as consequences of various interactions, such as those with drugs, lipids, and proteins, and their effects on transporter structure, biophysics, and physiology. We emphasize complementary techniques to gain a more complete understanding of transporter function. We are also asking whether ‘orphan’ transporters conduct Pi. This is an endeavor well- suited for our biochemical approach that exploits reconstituted systems. An aim is to develop ways to identify and/or contextualize the physiological functions of Pi transporters both in healthy and diseased states.