Introducing a special issue: Acid–base regulation and sensing in health and disease

Cell metabolism continuously generates acid, primarily in the form of H⁺ from fermentation and CO₂ from oxidative phosphorylation. However, the normal physiological functions at all levels of biological organization depend on pH being regulated within narrow ranges. The homeostatic regulation of acid–base status is therefore fundamentally important in virtually all aspects of physiology. At the cellular and organellar level, ion transport proteins import and export acids and bases across membranes, and passive H⁺-buffering systems limit changes in pH upon acid–base challenges and facilitate H⁺ movement to and from sites of production and transport. Signaling events—initiated, for example, by H⁺-sensing G-protein coupled receptors, ion channels, and transmembrane or soluble HCO₃⁻-sensing proteins¹—control the expression and activity of the pH regulatory systems and produce functional adaptations in response to acid–base disturbances. In vertebrates, acid extruded from cells enters the vasculature and moves via the blood to the lungs and kidneys where it is finally eliminated.

Given the pivotal physiological importance of acid–base regulation and its disturbances, it is not surprising that key studies on this topic have been published in Acta Physiologica. Over 120 years ago in 1904, when Acta Physiologica was the Skandinavisches Archiv Für Physiologie, August Krogh published pioneering organism-level experiments on cutaneous respiration, that is, the elimination of CO₂ across the frog skin.² Already then, studies of the physiological relevance of pH spanned from organism to molecule, as the same year, Christian Bohr, with Hasselbalch and Krogh, revealed how variation in CO₂ levels (with associated changes in pH) alter O₂ binding to hemoglobin.³ This essential observation, widely known as the Bohr effect, was the first demonstration that CO₂/H⁺ binding can alter protein function in a physiologically relevant manner. Since then, the concept of protonation as a posttranslational modification has been studied in great molecular detail. Important examples⁴ now illustrate how pH regulates the function of proteins with protonatable amino acid residues, from enzymes to ion channels to cell adhesion proteins. Thus, we now appreciate a complex landscape of pH sensitivity that extends far beyond the bona fide H⁺ sensing receptors.

More recent work highlights the essential roles that disturbances in acid–base regulation and sensing play in several pathophysiological conditions. This includes solid tumors characterized by extracellular accumulation of acidic metabolic waste products that have been shown to favor cancer progression and limit anti-cancer immunity.¹ The kidneys represent another important area in which pH disturbances are central to the pathology and of major societal impact.⁵ Finally, dysregulation of organellar pH emerges as a key dysfunction in several neurodegenerative diseases, from rare neurodevelopmental disorders to Alzheimer's and Parkinson's diseases.⁶

In 2010, a special issue in Acta Physiologica focused on acid–base transporters in intestinal electrolyte transport and how mucosal pH impacts gastrointestinal function.⁷ Since then, our understanding of acid–base transport has expanded in many important directions, through integrative functional studies of physiological and pathophysiological states and through the availability of cryo-EM structures of key human acid–base transporters.^{8, 9} Single-cell transcriptome and proteome data as well as lineage tracing for humans and model organisms now open up new understanding of the complex cellular interplay controlling acid–base homeostasis at the organ and organism level.

In the present special issue of Acta Physiologica, we aim to cover major current topics in acid–base regulation and sensing across physiology and pathophysiology. We welcome original research articles as well as review articles at any level from molecular to integrated organismal function. We look forward to receiving your contribution.

Both authors contributed equally.