The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

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 t...

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Bibliographic Details
Published in:The FASEB journal 2020-02, Vol.34 (2), p.3129-3150
Main Authors: Shi, Mingjun, Maique, Jenny, Shaffer, Joy, Davidson, Taylor, Sebti, Salwa, Fernández, Álvaro F., Zou, Zhongju, Yan, Shirley, Levine, Beth, Moe, Orson W., Hu, Ming Chang
Format: Article
Language:English
Subjects:
aging
Aging - metabolism
Animals
Autophagy
BCL2
beclin 1
Beclin-1 - deficiency
Beclin-1 - genetics
Female
fertility
Glucuronidase - genetics
Glucuronidase - metabolism
HEK293 Cells
Humans
Kidney - metabolism
Klotho Proteins
longevity
Male
Mice
NaPi cotransporter
Phosphates - metabolism
phosphorus
phosphotoxicity
Protein Binding
Proto-Oncogene Proteins c-bcl-2 - metabolism
αKlotho
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Summary: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.
ISSN:0892-6638
1530-6860
1530-6860
DOI:10.1096/fj.201902127R