Protoporphyrin IX accumulation disrupts mitochondrial dynamics and function in ABCG2-deficient hepatocytes

FEBS Lett. 2013 Oct 1;587(19):3202-9. doi: 10.1016/j.febslet.2013.08.011. Epub 2013 Aug 14.

Abstract

Targeted inhibition of multidrug ABCG2 transporter is believed to improve cancer therapeutics. However, the consequences of ABCG2 inhibition have not been systematically evaluated since ABCG2 is expressed in several organs including the liver. Here, we demonstrate that ABCG2-deficient hepatocytes have increased amounts of fragmental mitochondria accompanied by disruption of mitochondrial dynamics and functions. This disruption was due to ABCG2 knockout elevating intracellular protoporphyrin IX, which led to upregulation of DRP-1-mediated mitochondrial fission. The finding that ABCG2 deficiency can generate dysfunctional mitochondria in hepatocytes raises concerns regarding the systematic use of ABCG2 inhibitor in cancer patients.

Keywords: ABCG2; ATP-binding cassette transporter; Hepatocyte; Mitochondrial fission; PPIX; Protoporphyrin IX; protoporphyrin IX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / physiology*
  • Animals
  • Cells, Cultured
  • Glycogen / metabolism
  • Hepatocytes / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / metabolism*
  • Mitochondria, Liver / physiology
  • Mitochondrial Dynamics*
  • Protoporphyrins / metabolism*

Substances

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, mouse
  • Protoporphyrins
  • Glycogen
  • protoporphyrin IX