Glutaminolysis Shapes Cardiac Resilience to Stress via Mitochondrial Glutathione

BACKGROUND: Cardiac reserve is a strong predictor of cardiovascular morbidity and mortality, yet the metabolic mechanisms that enable the heart to mount an adaptive response to stress remain poorly understood. In this study, we sought to dissect the specific role of glutaminolysis, a key anaplerotic and redox-supporting pathway, in regulating cardiac reserve. METHODS: C] glutamine was performed in Langendorff-perfused hearts. A randomized, double-blind, placebo-controlled crossover trial of acute glutamine supplementation in healthy volunteers was conducted to evaluate translational relevance (ChiCTR2400082676). RESULTS: During acute stress, such as exercise or β-adrenergic stimulation, glutaminolysis was rapidly mobilized to supply mitochondrial glutathione, preserving mitochondrial redox homeostasis and sustaining cardiac contractile reserve. Mice with cardiomyocyte-specific deletion of glutaminase exhibited marked impairments in both contractile reserve and exercise capacity, accompanied by a failure to elevate mitochondrial glutathione and consequent mitochondrial oxidative stress. Chronic exercise training upregulated cardiac glutaminase expression and expanded the mitochondrial glutathione pool, linking this adaptive mechanism to training-induced improvements in cardiac reserve. In humans, acute oral glutamine supplementation enhanced cardiac reserve, as assessed by exercise stress echocardiography, in a placebo-controlled crossover design. CONCLUSIONS: These findings reveal a novel metabolic paradigm in which glutaminolysis functions as a dynamic pathway supporting mitochondrial health and cardiac resilience, and highlight glutamine supplementation as a potential therapeutic strategy to enhance cardiac reserve.