The mitochondrial calcium uniporter mediates mitochondrial Fe 2+ uptake and hepatotoxicity after acetaminophen.

Autor: Hu J; Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, United States of America; Departments of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States of America., Nieminen AL; Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, United States of America; Departments of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States of America; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States of America., Weemhoff JL; Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America., Jaeschke H; Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States of America., Murphy LG; Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, United States of America; Departments of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States of America., Dent JA; Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, United States of America; Departments of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States of America., Lemasters JJ; Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC, United States of America; Departments of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States of America; Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, United States of America; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States of America. Electronic address: JJLemasters@musc.edu.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2023 Nov 15; Vol. 479, pp. 116722. Date of Electronic Publication: 2023 Oct 15.
DOI: 10.1016/j.taap.2023.116722
Abstrakt: Acetaminophen (APAP) overdose disrupts hepatocellular lysosomes, which release ferrous iron (Fe 2+ ) that translocates into mitochondria putatively via the mitochondrial calcium uniporter (MCU) to induce oxidative/nitrative stress, the mitochondrial permeability transition (MPT), and hepatotoxicity. To investigate how MCU deficiency affects mitochondrial Fe 2+ uptake and hepatotoxicity after APAP overdose, global MCU knockout (KO), hepatocyte specific (hs) MCU KO, and wildtype (WT) mice were treated with an overdose of APAP both in vivo and in vitro. Compared to strain-specific WT mice, serum ALT decreased by 88 and 56%, respectively, in global and hsMCU KO mice at 24 h after APAP (300 mg/kg). Hepatic necrosis also decreased by 84 and 56%. By contrast, when MCU was knocked out in Kupffer cells, ALT release and necrosis were unchanged after overdose APAP. Intravital multiphoton microscopy confirmed loss of viability and mitochondrial depolarization in pericentral hepatocytes of WT mice, which was decreased in MCU KO mice. CYP2E1 expression, hepatic APAP-protein adduct formation, and JNK activation revealed that APAP metabolism was equivalent between WT and MCU KO mice. In cultured hepatocytes after APAP, loss of cell viability decreased in hsMCU KO compared to WT hepatocytes. Using fructose plus glycine to prevent cell killing, mitochondrial Fe 2+ increased progressively after APAP, as revealed with mitoferrofluor (MFF), a mitochondrial Fe 2+ indicator. By contrast in hsMCU KO hepatocytes, mitochondrial Fe 2+ uptake after APAP was suppressed. Rhod-2 measurements showed that Ca 2+ did not increase in mitochondria after APAP in either WT or KO hepatocytes. In conclusion, MCU mediates uptake of Fe 2+ into mitochondria after APAP and plays a central role in mitochondrial depolarization and cell death during APAP-induced hepatotoxicity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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