Alcohol-induced CYP2E1, mitochondrial dynamics and retrograde signaling in human hepatic 3D organoids. Free Radic Biol Med 2020 Nov 01;159:1-14
Date
08/02/2020Pubmed ID
32738395DOI
10.1016/j.freeradbiomed.2020.06.030Scopus ID
2-s2.0-85089013403 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
Alcohol toxicity is a significant health problem with ~3 million estimated deaths per year globally. Alcohol is metabolized to the toxic metabolite, acetaldehyde by alcohol dehydrogenase or CYP2E1 in the hepatic tissue, and also induces reactive oxygen species (ROS), which together play a pivotal role in cell and tissue damage. Our previous studies with COS-7 cells transduced with unique human CYP2E1 variants that mostly localize to either microsomes or mitochondria revealed that mitochondrially-localized CYP2E1 drives alcohol toxicity through the generation of higher levels of ROS, which has a consequent effect on cytochrome c oxidase (CcO) and mitochondrial oxidative function. Alcohol treatment of human hepatocyte cell line, HepaRG, in monolayer cultures increased ROS, affected CcO activity/stability, and induced mitophagy. Alcohol treatment of 3D organoids of HepaRG cells induced higher levels of CYP2E1 mRNA and activated mitochondrial stress-induced retrograde signaling, and also induced markers of hepatic steatosis. Knock down of CYP2E1 mRNA using specific shRNA, FK506, a Calcineurin inhibitor, and Mdivi-1, a DRP1 inhibitor, ameliorated alcohol-induced mitochondrial retrograde signaling, and hepatic steatosis. These results for the first time present a mechanistic link between CYP2E1 function and alcohol mediated mitochondrial dysfunction, retrograde signaling, and activation of hepatic steatosis in a 3D organoid system that closely recapitulates the in vivo liver response.
Author List
Angireddy R, Chowdhury AR, Zielonka J, Ruthel G, Kalyanaraman B, Avadhani NGAuthors
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinJacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Cytochrome P-450 CYP2E1Humans
Liver
Mitochondrial Dynamics
Organoids
Oxidative Stress
