title: AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function.
abstract: Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury.
authors: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors: Sun Woo Sophie
authors: SW
authors: Kang
authors: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors: Ghada
authors: G
authors: Haydar
authors: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors: Caitlin
authors: C
authors: Taniane
authors: Liver Research Group, Australian National University Medical School, Canberra, Australia.
authors: Geoffrey
authors: G
authors: Farrell
authors: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
authors: Irwin M
authors: IM
authors: Arias
authors: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, United States of America.
authors: Jennifer
authors: J
authors: Lippincott-Schwartz
authors: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors: Dong
authors: D
authors: Fu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000082:Acetaminophen / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control*; D004008:Diclofenac / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology*
chemical_list: D012265:Ribonucleotides; D004008:Diclofenac; D000620:Aminoimidazole Carboxamide; D000082:Acetaminophen; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide