| First Author | Shi M | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 2 | Pages | 3129-3150 |
| PubMed ID | 31908069 | Mgi Jnum | J:298153 |
| Mgi Id | MGI:6469815 | Doi | 10.1096/fj.201902127R |
| Citation | Shi M, et al. (2020) The tripartite interaction of phosphate, autophagy, and alphaKlotho in health maintenance. FASEB J 34(2):3129-3150 |
| abstractText | Aging-related organ degeneration is driven by multiple factors including the cell maintenance mechanisms of autophagy, the cytoprotective protein alphaKlotho, and the lesser known effects of excess phosphate (Pi), or phosphotoxicity. To examine the interplay between Pi, autophagy, and alphaKlotho, we used the BK/BK mouse (homozygous for mutant Becn1(F121A) ) with increased autophagic flux, and alphaKlotho-hypomorphic mouse (kl/kl) with impaired urinary Pi excretion, low autophagy, and premature organ dysfunction. BK/BK mice live longer than WT littermates, and have heightened phosphaturia from downregulation of two key NaPi cotransporters in the kidney. The multi-organ failure in kl/kl mice was rescued in the double-mutant BK/BK;kl/kl mice exhibiting lower plasma Pi, improved weight gain, restored plasma and renal alphaKlotho levels, decreased pathology of multiple organs, and improved fertility compared to kl/kl mice. The beneficial effects of heightened autophagy from Becn1(F121A) was abolished by chronic high-Pi diet which also shortened life span in the BK/BK;kl/kl mice. Pi promoted beclin 1 binding to its negative regulator BCL2, which impairs autophagy flux. Pi downregulated alphaKlotho, which also independently impaired autophagy. In conclusion, Pi, alphaKlotho, and autophagy interact intricately to affect each other. Both autophagy and alphaKlotho antagonizes phosphotoxicity. In concert, this tripartite system jointly determines longevity and life span. |
