Na(+)/H(+) antiporter (NHE1) and lactate/H(+) symporters (MCTs) in pH homeostasis and cancer metabolism

Biochim Biophys Acta. 2016 Oct;1863(10):2465-80. doi: 10.1016/j.bbamcr.2016.02.018. Epub 2016 Mar 2.


The Na(+)/H(+)-exchanger NHE1 and the monocarboxylate transporters MCT1 and MCT4 are crucial for intracellular pH regulation, particularly under active metabolism. NHE1, a reversible antiporter, uses the energy provided by the Na(+) gradient to expel H(+) ions generated in the cytosol. The reversible H(+)/lactate(-) symporters MCT1 and 4 cotransport lactate and proton, leading to the net extrusion of lactic acid in glycolytic tumors. In the first two sections of this article we review important features and remaining questions on the structure, biochemical function and cellular roles of these transporters. We then use a fully-coupled mathematical model to simulate their relative contribution to pH regulation in response to lactate production, as it occurs in highly hypoxic and glycolytic tumor cells. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Keywords: Cancer; Lactate transporters; MCTs; Mathematical model; Membrane transporters; NHE1; pH regulation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biological Transport, Active
  • Cation Transport Proteins / antagonists & inhibitors
  • Cation Transport Proteins / chemistry
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / physiology*
  • Glycolysis
  • Homeostasis
  • Humans
  • Hydrogen / metabolism*
  • Hydrogen-Ion Concentration*
  • Ion Transport
  • Lactic Acid / metabolism*
  • Models, Biological
  • Models, Molecular
  • Monocarboxylic Acid Transporters / physiology*
  • Muscle Proteins / physiology*
  • Mutation
  • Neoplasm Proteins / physiology*
  • Neoplasms / metabolism*
  • Protein Conformation
  • Sodium / metabolism*
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers / antagonists & inhibitors
  • Sodium-Hydrogen Exchangers / chemistry
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / physiology*
  • Symporters / physiology*


  • Cation Transport Proteins
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • Neoplasm Proteins
  • SLC16A4 protein, human
  • SLC9A1 protein, human
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • Symporters
  • monocarboxylate transport protein 1
  • Lactic Acid
  • Hydrogen
  • Sodium