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TMEM174 Deficiency Reduces Longevity by Promoting Phosphate-Driven Vascular Calcification
Jose G Miranda1, Judith Blaine1, Makoto Miyazaki1
1Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO USA.
Background:
Dysregulation of phosphate homeostasis contributes to reduced longevity and vascular complications in chronic kidney disease and aging. This study investigates the role of TMEM174, a proximal tubule-specific protein, in regulating the phosphate co-transporter NPT2A and its subsequent impact on lifespan and vascular health.
Methods:
TMEM174 knockout (KO) mice (C57BL6/J and DBA/2J) were fed diets with varying phosphate concentrations (0.6% vs. 1.2%). In OKP cells, TIRF and FRET microscopy, alongside immunoprecipitation, were used to identify the TMEM174 protein regions essential for NPT2A binding and endocytosis.
Results:
TMEM174 KO mice exhibited significantly shorter lifespans than wild-type controls. High phosphate diets exacerbated vascular calcification, stiffness, and mortality, while low phosphate diets rescued these phenotypes. In vitro, TMEM174 siRNA blocked PTH-induced NPT2A endocytosis, increasing its apical membrane retention. FRET and biochemical assays revealed that the C-terminal region of TMEM174 is essential for its association with NPT2A. While intact TMEM174 and N-terminal mutants (TMEM174ΔN) facilitated NPT2A degradation, C-terminal deletions (TMEM174ΔC) failed to associate with or degrade NPT2A.
Conclusions:
TMEM174 is a critical regulator of phosphate homeostasis and longevity. The C-terminal region of TMEM174 is specifically required for NPT2A endocytosis and degradation, identifying it as a potential therapeutic target for managing phosphate-related vascular complications.
