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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

This summary is machine-generated.

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.

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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.