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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.

Research Square

|June 12, 2026

Summary

This summary is machine-generated.

TMEM174 protein is vital for phosphate balance and longevity. Its C-terminal region regulates phosphate transporter NPT2A endocytosis and degradation, offering a therapeutic target for vascular complications.

Keywords:

TMEM174 longevity phosphate homeostasis vascular calcification

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Area of Science:

Nephrology
Molecular Biology
Gerontology

Background:

Phosphate homeostasis is crucial for preventing vascular issues and extending lifespan, particularly in chronic kidney disease and aging.
TMEM174, a protein in the kidney's proximal tubules, influences phosphate transport and overall health.

Purpose of the Study:

To investigate TMEM174's role in regulating the phosphate co-transporter NPT2A.
To determine TMEM174's impact on lifespan and vascular health.
To identify specific TMEM174 regions involved in NPT2A binding and endocytosis.

Main Methods:

Utilized TMEM174 knockout mice fed varying phosphate diets.
Employed TIRF and FRET microscopy, and immunoprecipitation in OKP cells.
Analyzed NPT2A endocytosis, degradation, and membrane retention via siRNA and biochemical assays.

Main Results:

TMEM174 knockout mice had significantly reduced lifespans.
High phosphate diets worsened vascular calcification and mortality, while low phosphate diets improved outcomes.
The C-terminal region of TMEM174 is essential for NPT2A binding, endocytosis, and degradation.

Conclusions:

TMEM174 is a critical regulator of phosphate homeostasis and longevity.
Targeting the TMEM174 C-terminus could mitigate phosphate-related vascular complications.