Protoporphyrin IX accumulation disrupts mitochondrial dynamics and function in ABCG2-deficient hepatocytes
Journal
FEBS Letters
Journal Volume
587
Journal Issue
19
Pages
3202-3209
Date Issued
2013
Author(s)
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. ? 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Subjects
ABCG2; Hepatocyte; Mitochondrial fission; Protoporphyrin IX
SDGs
Other Subjects
adenosine triphosphate; breast cancer resistance protein; dynamin; Dynamin related protein 1; glycogen; protoporphyrin; unclassified drug; article; controlled study; liver cell; mitochondrial dynamics; mitochondrial fission; mitochondrial membrane potential; mitochondrial respiration; mouse; nonhuman; oxidative phosphorylation; oxygen consumption; priority journal; upregulation; ABCG2; ATP-binding cassette transporter; Hepatocyte; Mitochondrial fission; PPIX; protoporphyrin IX; Protoporphyrin IX; Animals; ATP-Binding Cassette Transporters; Cells, Cultured; Glycogen; Hepatocytes; Mice; Mice, Knockout; Mitochondria, Liver; Mitochondrial Dynamics; Protoporphyrins
Type
journal article