Lactate production can function to increase human epithelial cell iron concentration

Abstract

Iron is an essential micronutrient required by every cell, inclusive of both prokaryotes and eukaryotes. Under conditions of limited iron availability, plants and microbes evolved mechanisms to acquire iron which include carbon metabolism reprogramming, with the activity of several enzymes involved in the Krebs cycle and the glycolytic pathway being stimulated by metal deficiency. Following release, resultant carboxylates/hydroxycarboxylates can function as ligands to complex iron and facilitate its solubilization and uptake, reversing the deficiency. Human epithelial tissue may produce lactate, a hydroxycarboxylate, during absolute and functional iron deficiency in an attempt to import metal to reverse limited availability. Here we investigate 1) if lactate can increase cell metal import, 2) if lactic dehydrogenase (LDH) activity in and lactate production by cells correspond to metal availability, and 3) if blood concentrations of LDH in a human cohort correlate with indices of iron homeostasis. Exposures of Caco-2 cells to both Na lactate and ferric ammonium citrate (FAC) increased metal import relative to FAC alone. Fumaric, isocitric, malic, and succinic acid exposure revealed that FAC co-incubation similarly increased iron import relative to FAC alone. Increased iron import following exposures to Na lactate and FAC elevated both ferritin and metal associated with mitochondria. LDH in Caco-2 cell scrapings did not change after exposure to deferoxamine but decreased with 24 hr exposure to FAC. Lactate levels in both the supernatants and cell scrapings revealed decreased levels at 4, 8, and 24 hr with FAC. In the National Health and Nutrition Examination Survey (NHANES 2005-2010), Spearman correlations demonstrated significant negative relationships between LDH concentrations and serum iron. We conclude that iron import in human cells can involve lactate, LDH activity can reflect the availability of this metal, and blood LDH concentrations can correlate with indices of iron homeostasis.