TY - JOUR
T1 - The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance
AU - Shi, Mingjun
AU - Maique, Jenny
AU - Shaffer, Joy
AU - Davidson, Taylor
AU - Sebti, Salwa
AU - Fernández, Álvaro F.
AU - Zou, Zhongju
AU - Yan, Shirley
AU - Levine, Beth
AU - Moe, Orson W.
AU - Hu, Ming Chang
N1 - Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Aging-related organ degeneration is driven by multiple factors including the cell maintenance mechanisms of autophagy, the cytoprotective protein αKlotho, and the lesser known effects of excess phosphate (Pi), or phosphotoxicity. To examine the interplay between Pi, autophagy, and αKlotho, we used the BK/BK mouse (homozygous for mutant Becn1F121A) with increased autophagic flux, and αKlotho-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 αKlotho levels, decreased pathology of multiple organs, and improved fertility compared to kl/kl mice. The beneficial effects of heightened autophagy from Becn1F121A 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 αKlotho, which also independently impaired autophagy. In conclusion, Pi, αKlotho, and autophagy interact intricately to affect each other. Both autophagy and αKlotho antagonizes phosphotoxicity. In concert, this tripartite system jointly determines longevity and life span.
AB - Aging-related organ degeneration is driven by multiple factors including the cell maintenance mechanisms of autophagy, the cytoprotective protein αKlotho, and the lesser known effects of excess phosphate (Pi), or phosphotoxicity. To examine the interplay between Pi, autophagy, and αKlotho, we used the BK/BK mouse (homozygous for mutant Becn1F121A) with increased autophagic flux, and αKlotho-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 αKlotho levels, decreased pathology of multiple organs, and improved fertility compared to kl/kl mice. The beneficial effects of heightened autophagy from Becn1F121A 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 αKlotho, which also independently impaired autophagy. In conclusion, Pi, αKlotho, and autophagy interact intricately to affect each other. Both autophagy and αKlotho antagonizes phosphotoxicity. In concert, this tripartite system jointly determines longevity and life span.
KW - BCL2
KW - NaPi cotransporter
KW - aging
KW - autophagy
KW - beclin 1
KW - fertility
KW - longevity
KW - phosphorus
KW - phosphotoxicity
KW - αKlotho
UR - http://www.scopus.com/inward/record.url?scp=85078748363&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078748363&partnerID=8YFLogxK
U2 - 10.1096/fj.201902127R
DO - 10.1096/fj.201902127R
M3 - Article
C2 - 31908069
AN - SCOPUS:85078748363
SN - 0892-6638
VL - 34
SP - 3129
EP - 3150
JO - FASEB Journal
JF - FASEB Journal
IS - 2
ER -