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Emerging and established modes of cell death during acetaminophen-induced liver injury

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A Letter to the Editor, News and Views to this article was published on 02 April 2020

Abstract

Acetaminophen (APAP)-induced liver injury is an important clinical and toxicological problem. Understanding the mechanisms and modes of cell death are vital for the development of therapeutic interventions. The histological and clinical features of APAP hepatotoxicity including cell and organelle swelling, karyolysis, and extensive cell contents release lead to the characterization of the cell death as oncotic necrosis. However, the more recent identification of detailed signaling mechanisms of mitochondrial dysfunction, the amplification mechanisms of mitochondrial oxidant stress and peroxynitrite formation by a mitogen-activated protein kinase cascade, mechanisms of the mitochondrial permeability transition pore opening and nuclear DNA fragmentation as well as the characterization of the sterile inflammatory response suggested that the mode of cell death is better termed programmed necrosis. Additional features like mitochondrial Bax translocation and cytochrome c release, mobilization of lysosomal iron and the activation of receptor-interacting protein kinases and the inflammasome raised the question whether other emerging modes of cell death such as apoptosis, necroptosis, ferroptosis and pyroptosis could also play a role. The current review summarizes the key mechanisms of APAP-induced liver injury and compares these with key features of the newly described modes of cell death. Based on the preponderance of experimental and clinical evidence, the mode of APAP-induced cell death should be termed programmed necrosis; despite some overlap with other modes of cell death, APAP hepatotoxicity does not fulfill the characteristics of either apoptosis, necroptosis, ferroptosis, pyroptosis or autophagic cell death.

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Abbreviations

AIF:

Apoptosis-inducing factor

AIM2:

Absent in melanoma 2

APAF-1:

Apoptotic protease-activating factor-1

APAP:

Acetaminophen

ASK1:

Apoptosis signal-regulating kinase 1

CAD:

Caspase-activted DNase

DAMP:

Damage-associated molecular pattern

DMSO:

Dimethylsulfoxide

GFP:

Green fluorescence protein

GPx:

Glutathione peroxidase

GSK-3b:

Glycogen synthase kinase 3 beta

HETEs:

Hydroxy-eicosatetraenoic acids

IAP:

Inhibitor of apoptosis

ICAD:

Inhibitor of caspase-activated DNase

IL-1:

Interleukin-1

JNK:

c-Jun N-terminal kinase

LPO:

Lipid peroxidation

MAPK:

Mitogen-activating protein kinase

MKK4:

Mitogen-activated protein kinase kinase 4

MLK3:

Mixed-lineage kinase 3

MLKL:

Mixed lineage kinase domain-like protein

MPTP:

Mitochondrial membrane permeability transition pore

mtDNA:

Mitochondrial DNA

Nalp3:

NACHT, LRR and PYD domain-containing protein

NAPQI:

N-acetyl-p-benzoquinone imine

NCOA4:

Nuclear receptor coactivator 4

PAMP:

Pathogen-associated molecular pattern

PINK1:

PTEN-induced kinase 1

PTEN:

Phosphatase and tensin homolog

RIPK:

Receptor-interacting protein kinase

Smac/Diablo:

Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI

SQSTM1/p62:

Sequestosome 1/p62

TLR:

Toll-like receptor

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

TFEB:

Transcription factor EB

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Acknowledgements

This work was supported in part by National Institutes of Health Grants R01 DK102142, R01 DK070195, P20 GM103549 and P30 GM118247.

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  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA

    Hartmut Jaeschke, Anup Ramachandran, Xiaojuan Chao & Wen-Xing Ding

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  1. Hartmut Jaeschke
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  2. Anup Ramachandran
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  3. Xiaojuan Chao
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  4. Wen-Xing Ding
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Correspondence to Hartmut Jaeschke.

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H Jaeschke received grant support from McNeil Consumer Health, Inc. All the other authors declare no conflict of interest.

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Jaeschke, H., Ramachandran, A., Chao, X. et al. Emerging and established modes of cell death during acetaminophen-induced liver injury. Arch Toxicol 93, 3491–3502 (2019). https://doi.org/10.1007/s00204-019-02597-1

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  • DOI: https://doi.org/10.1007/s00204-019-02597-1

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