In kidney disease, phosphate flips a glutamine switch that strains heart mitochondria — and blocking it protected hearts in mice

Edited by Samael A. Tejada, Founder & Editor-in-Chief

Kidney failure quietly remodels the heart, and cardiologists have long treated that enlargement as a pressure problem. This study makes it a fuel problem: a mineral that kidneys fail to clear reaches into heart mitochondria and changes what they burn. The chain is specific enough to block — in mice, blocking it worked.

What did the study actually find?

The team combined transcriptomic, metabolomic and proteomic profiling to ask what changes in the heart when kidneys fail. Their answer centered on glutaminase 1 (GLS1), the enzyme inside mitochondria that converts glutamine into glutamate and feeds it into energy production. Phosphate — a mineral that accumulates in the blood in chronic kidney disease — emerged as a major regulator of both GLS1 activity and expression. With GLS1 switched up, heart-muscle cells burned more glutamine, produced more ammonia, and showed disrupted expression of mitochondrial respiratory proteins, disturbed redox balance and reduced bioenergetic efficiency: the mitochondria made energy less well while the heart grew larger.

What happened when GLS1 was blocked?

Two interventions, both in male C57BL/6J mice with kidney disease. In one, GLS1 was deleted specifically in cardiomyocytes, the heart's muscle cells. In the other, GLS1 was inhibited pharmacologically. Both attenuated the left ventricular hypertrophy that kidney disease otherwise produced. That is a genuine causal test of the pathway in this model — and its boundary is equally clear: male mice, one kidney-disease model, and a hypertrophy endpoint, not survival or heart-failure outcomes. The authors describe GLS1 as a potential therapeutic target, and the word potential is doing real work in that sentence.

What do the human data add — and what don't they?

Two human threads, both associative. In a multicenter cohort of peritoneal dialysis patients, the GLS1 activity that patients' serum induced was associated with left ventricular hypertrophic remodeling — the human echo of the mouse mechanism. Separately, human myocardial samples from people with chronic kidney disease showed increased GLS1 expression. Neither thread shows that blocking GLS1 helps a human heart: no person in this study received a GLS1 inhibitor, and association in dialysis patients cannot separate GLS1 as a cause from GLS1 as a marker of sicker kidneys and higher phosphate. What the human data do is keep the mouse story from being only a mouse story.

Where the evidence stands

• Established: Chronic kidney disease commonly leads to left ventricular hypertrophy, a major driver of cardiovascular death in kidney patients; phosphate accumulates as kidney function falls; and GLS1 is the mitochondrial enzyme that gates glutamine use (glutaminolysis) in cells.
• Preliminary: In male mice with kidney disease (Nature Communications, Nov 1, 2026; DOI 10.1038/s41467-026-79129-w), phosphate-driven GLS1 activation increased ammonia, disrupted mitochondrial respiratory proteins and redox homeostasis and reduced bioenergetic efficiency, and cardiomyocyte GLS1 deletion or pharmacological inhibition attenuated hypertrophy. Human support is associative: serum-induced GLS1 activity tracked hypertrophic remodeling in a multicenter peritoneal dialysis cohort, and CKD heart tissue showed increased GLS1 expression.
• Absent: Any human intervention data, female-animal data, survival or heart-failure endpoints, and independent replication of the phosphate-GLS1 axis.