Abstract
How inorganic phosphate (Pi) homeostasis is regulated in Drosophila is currently unknown. We here identify MFS2 as a key Pi transporter in fly renal (Malpighian) tubules. Consistent with its role in Pi excretion, we found that dietary Pi induces MFS2 expression. This results in the formation of Malpighian calcium-Pi stones, while RNAi-mediated knockdown of MFS2 increases blood (hemolymph) Pi and decreases formation of Malpighian tubule stones in flies cultured on high Pi medium. Conversely, microinjection of adults with the phosphaturic human hormone fibroblast growth factor 23 (FGF23) induces tubule expression of MFS2 and decreases blood Pi. This action of FGF23 is blocked by genetic ablation of MFS2. Furthermore, genetic overexpression of the fly FGF branchless (bnl) in the tubules induces expression of MFS2 and increases Malpighian tubule stones suggesting that bnl is the endogenous phosphaturic hormone in adult flies. Finally, genetic ablation of MFS2 increased fly life span, suggesting that Malpighian tubule stones are a key element whereby high Pi diet reduces fly longevity previously reported by us. In conclusion, MFS2 mediates excretion of Pi in Drosophila, which is as in higher species under the hormonal control of FGF-signaling.
Highlights
Phosphate is required for many important cellular processes and having too little phosphate or too much can cause disease and reduce lifespan in humans[1,2,3]
This role of MFS2 may be under the control of FGF-signaling to maintain blood Pi homeostasis as it is in higher species
To begin to understand why flies die when exposed to high dietary Pi21,22 we first determined hemolymph Pi in young and in aged flies on standard medium (C), medium supplemented with 30 mM sodium phosphate (P30) or medium supplemented with 5 mM phosphonoformic acid (PFA), an antiviral drug that blocks Pi transporters, and which extends fly life span[21]
Summary
Phosphate is required for many important cellular processes and having too little phosphate (hypophosphatemia) or too much (hyperphosphatemia) can cause disease and reduce lifespan in humans[1,2,3]. Tubule xanthine[17], calcium oxalate[18] and urate[19] stone formation caused by genetic knockdown or overexpression markedly reduce fly lifespan. Using this model organism, novel insights about electrolyte homeostasis were obtained. When dietary Pi is restricted by addition of sevelamer to the culture medium or when cellular uptake of Pi is reduced after treatment with PFA, even otherwise normal adult flies live longer[21,22]. In light of its high translational relevance, we here further characterized fly Pi homeostasis and show that a high Pi diet stimulates formation of Malpighian tubule stones These stones likely contribute to reduced longevity of adult flies when cultured on high Pi medium. This role of MFS2 may be under the control of FGF-signaling to maintain blood Pi (hemolymph Pi) homeostasis as it is in higher species
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