title: Protoporphyrin IX accumulation disrupts mitochondrial dynamics and function in ABCG2-deficient hepatocytes.
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.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
authors: Yu-Hsing
authors: YH
authors: Lin
authors: Hsiao-Min
authors: HM
authors: Chang
authors: Fang-Pei
authors: FP
authors: Chang
authors: Chia-Rui
authors: CR
authors: Shen
authors: Chao-Lin
authors: CL
authors: Liu
authors: Wan-Yu
authors: WY
authors: Mao
authors: Chung-Chih
authors: CC
authors: Lin
authors: Hsuan-Shu
authors: HS
authors: Lee
authors: Chia-Ning
authors: CN
authors: Shen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000502:physiology; D063154:Mitochondrial Dynamics; D011524:Protoporphyrins / Q000378:metabolism*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D011524:Protoporphyrins; D006003:Glycogen; C028025:protoporphyrin IX
keywords: ABCG2; ATP-binding cassette transporter; Hepatocyte; Mitochondrial fission; PPIX; Protoporphyrin IX; protoporphyrin IX