Hypercapnia Induces Mitochondrial Adaptations and Alters Glutamine Metabolism to Drive a Distinct Metabolic Phenotype in Monocytes.

Carbon dioxide (CO2) is an ancient and ubiquitous physiological gas generated during aerobic respiration. Historically viewed as a simple metabolic waste product, CO2 has received far less research attention than oxygen (O2), the primary substrate of aerobic respiration. However, emerging evidence has revealed important roles for CO2 in immunometabolism, immunology, muscle physiology, and clinical medicine. While circulating pCO2 levels are tightly regulated, patients with lung diseases such as chronic obstructive pulmonary disease (COPD) frequently develop hypercapnia, pCO2 > 45 mmHg. Hypercapnia is associated with significantly increased mortality, higher risk of ICU admission, and a global prevalence estimated at 13-15 million patients. Its broader clinical consequences remain poorly understood and are inadequately integrated into current therapeutic paradigms. Here, we examined the impact of hypercapnia on the metabolic profile of monocytes. We demonstrate that 24 h of buffered hypercapnia induces a marked reduction in mitochondrial mass. This is accompanied by dysregulation of mitochondrial membrane potential and key bioenergetic substrates (NADH/NAD+ and ATP content). We further show that hypercapnia alters the abundance of metabolites and proteins associated with mitochondrial metabolism, with effects spanning glucose, glutamine, and lipid metabolism. Thus, we provide direct mechanistic evidence that hypercapnia directly alters the glutamine-glutamate-proline synthesis axis. Collectively, these findings establish the foundation for a discrete hypercapnic metabolic phenotype, that is, in several respects, distinct from the metabolic adaptations observed in hypoxia. We propose that hypercapnia triggers a cascade of metabolic adaptations with tissue-dependent consequences on cellular effector functions.