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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.
Insights
TMEM174 protein regulates phosphate levels, impacting lifespan and vascular health. Its C-terminal region is key for controlling phosphate transporter NPT2A, offering a therapeutic target for related complications.
Area of Science:
- Nephrology
- Molecular Biology
- Longevity Research
Background:
- Phosphate homeostasis is crucial for preventing vascular issues in chronic kidney disease and aging.
- Dysregulation of phosphate balance is linked to reduced lifespan and cardiovascular complications.
Purpose of the Study:
- Investigate the role of TMEM174 in regulating the phosphate co-transporter NPT2A.
- Determine TMEM174's impact on lifespan and vascular health.
Main Methods:
- Utilized TMEM174 knockout mice fed varying phosphate diets.
- Employed microscopy (TIRF, FRET) and immunoprecipitation in OKP cells.
- Identified critical TMEM174 protein regions for NPT2A interaction and endocytosis.
Main Results:
- TMEM174 knockout mice showed reduced lifespan, worsened by high phosphate diets.
- Low phosphate diets improved vascular health and survival in knockout mice.
- TMEM174's C-terminal region is essential for NPT2A binding, endocytosis, and degradation.
Conclusions:
- TMEM174 is vital for maintaining phosphate homeostasis and longevity.
- The C-terminal region of TMEM174 is specifically required for NPT2A regulation.
- Targeting TMEM174 offers a potential therapeutic strategy for phosphate-related vascular diseases.
