A new paper, co authored by Virgilio Lew, suggests a possible origin for the unknown acid source causing metabolic acidosis in sickle cell anaemia patients, a condition often associated with clinical severity and pain crises.
Sickle cell anaemia, caused by the homozygous inheritance of the mutant haemoglobin S (HbS), is a highly debilitating disease affecting millions worldwide. A frequent complication in this disease is metabolic acidosis, caused by the accumulation of lactate, particularly severe in patients with compromised liver and kidney function that cannot adequately metabolize or excrete the accumulated lactate. A major difficulty with therapeutic interventions in the past had been the unknown source of the lactate, the long-standing mystery our study attempted to solve. The results showed that the same mechanism that causes deoxygenated sickle red blood cells to deform, dehydrate and block small vessels in the circulation of patients makes the sickle cells become profuse and relentless lactate producers, as illustrated in the figure.
Deoxygenation of HbS keeps the Piezo1 channels open during sickle cell transits in the systemic venous bloodstream highly increasing the pump-leak turnover of calcium and sodium ions via ATP-consuming calcium (PMCA) and Na/K (ATP1) pumps. ATP levels of sickle cells had been shown to stay firmly within normal ranges indicating that the vast amounts of ATP consumed by the pumps are rapidly restored by glycolysis, a cycle that generates one molecule of lactate per molecule of ATP restored. Most of the lactate thus produced exits the cells to the plasma by the monocarboxylate transport pathway (MCT), imposing a constant extra supply of lactate to the organism.
These results bring into sharp focus the first step in this cycle, the molecular interaction between deoxy-HbS and Piezo1 that transiently disables the spontaneous inactivation of these channels in the deoxy circulation. The deoxy-HbS-Piezo1 interaction and the Piezo1 inactivation disablement mechanisms are thus prime research targets for elucidating the pathophysiology of sickle cell disease and for seeking new therapies.