The AMPKγ1 Subunit Plays an Essential Role in Erythrocyte Membrane Elasticity, and Its Genetic Inactivation Induces Splenomegaly and Anemia

FASEB J. 2011 Jan;25(1):337-47. doi: 10.1096/fj.10-169383. Epub 2010 Sep 29.

Abstract

AMP-activated protein kinase (AMPK) is an αβγ heterotrimer conserved throughout evolution and important for energy sensing in all eukaryote cells. AMPK controls metabolism and various cellular events in response to both hormones and changes in cellular energy status. The γ subunit senses intracellular energy status through the competitive binding of AMP and ATP. We show here that targeted disruption of the mouse AMPKγ1 gene (Prkag1) causes regenerative hemolytic anemia by increasing the sequestration of abnormal erythrocytes. Prkag1(-/-) mice displayed splenomegaly and iron accumulation due to compensatory splenic erythropoiesis and erythrophagocytosis. Moreover, AMPKγ1-deficient erythrocytes were highly resistant to osmotic hemolysis and poorly deformable in response to increasing shear stress, consistent with greater membrane rigidity. No change in cytoskeletal protein composition was observed; however, the phosphorylation level of adducin, a protein promoting the binding of spectrin to actin, was higher in AMPKγ1-deficient erythrocytes. Together, these results demonstrate that AMPKγ1 subunit is required for the maintenance of erythrocyte membrane elasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Anemia / blood
  • Anemia / enzymology*
  • Anemia / genetics
  • Anemia, Hemolytic / enzymology
  • Anemia, Hemolytic / genetics
  • Animals
  • Blotting, Western
  • Elasticity
  • Erythroblasts / metabolism
  • Erythroblasts / pathology
  • Erythrocyte Count
  • Erythrocyte Deformability
  • Erythrocyte Membrane / metabolism*
  • Female
  • Hyperplasia
  • Iron / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Spleen / metabolism
  • Spleen / pathology
  • Splenomegaly / blood
  • Splenomegaly / enzymology*
  • Splenomegaly / genetics

Substances

  • Membrane Proteins
  • Prkag1 protein, mouse
  • Iron
  • AMPK alpha1 subunit, mouse
  • AMPK alpha2 subunit, mouse
  • Prkab1 protein, mouse
  • AMP-Activated Protein Kinases