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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.
Biorxiv : the Preprint Server for Biology
|April 27, 2026
Summary
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.
