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The Critical Role of Mitochondria in Drug-Induced Liver Injury

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Molecules, Systems and Signaling in Liver Injury

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a rare form of liver injury that occurs in patients taking therapeutic doses of drugs. While idiosyncratic hepatotoxic drugs are not structurally or chemically related, most drugs that cause DILI have been shown to “stress” mitochondria through inhibition of mitochondrial respiration, increased mitochondrial reactive oxygen species (ROS) generation, and other changes that disrupt mitochondrial homeostasis. In most cases, hepatocytes adapt to drug-induced mitochondrial stress by activating adaptation signaling pathways, including mitochondrial adaptive responses such as autophagy/mitophagy, mitochondrial remodeling, and alterations in mitochondrial fusion-fission. Due to these adaptations, drug intake alone is not sufficient to cause liver injury, with acetaminophen being the notable exception. Idiosyncratic DILI involves other extrinsic factors, including inflammation and the adaptive immune system. Inflammation may promote DILI because mitochondrial stress (i.e., increased mitochondrial ROS generation) induced by hepatotoxic drugs can inhibit adaptation/survival signaling pathways, such as NF-κB, needed to withstand the cytotoxic effects of tumor necrosis factor-α (TNF) released during inflammation. If mitochondrial and hepatocellular injury reach a critical threshold, death signaling pathways involving c-Jun N-terminal kinase (JNK) that target mitochondria become activated. Binding of activated JNK to mitochondria triggers the mitochondrial permeability transition (MPT) that results in hepatocyte death and liver injury. Mitochondria, therefore, play a critical role in all stages of DILI.

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Abbreviations

ALT:

Alanine aminotransferase

AMPK:

AMP-activated protein kinase

APAP:

Acetaminophen

ARE:

Antioxidant response element

ASK1:

Apoptosis signal-regulating kinase 1

Bcl-2:

B-cell lymphoma-2

Cu3:

Cullin-dependent E3 ubiquitin ligase complex

CYP450:

Cytochrome P450

DILI:

Drug-induced liver injury

Drp1:

Dynamin-related protein 1

GCL:

Glutamate cysteine ligase

GSH:

Glutathione

GSK-3β:

Glycogen synthase kinase-3β

GWAS:

Genome-wide association studies

HLA:

Human leukocyte antigen

JNK:

c-Jun N-terminal kinase

Keap1:

Kelch-like ECH-associated protein 1

LPS:

Lipopolysaccharide

Mcl-1:

Induced myeloid leukemia cell differentiation protein

Mfn:

Mitofusin

MLK3:

Mixed-lineage kinase-3

MOMP:

Mitochondrial outer membrane permeabilization

MPT:

Mitochondrial permeability transition

NAPQI:

N-Acetyl-p-benzo-quinoneimine

Nrf-2:

Nuclear factor (erythroid-derived 2)-like-2

Opa1:

Optic atrophy 1

PGC-1α:

Proliferator-activated receptor gamma coactivator-1α

PKC:

Protein kinase C

RIP1:

Receptor-interacting serine/threonine-protein kinase 1

ROS:

Reactive oxygen species

Sab:

SH3 homology associated BTK-binding protein

SOD:

Superoxide dismutase

TNF:

Tumor necrosis factor-α

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Authors and Affiliations

  1. Department of Biopharmaceutical Sciences, School of Pharmacy, Keck Graduate Institute, 535 Watson Drive, Claremont, California, CA, 91711, USA

    Carl W. Decker, Joseph G. Casian, Kim Tho Nguyen & Derick Han

  2. W.M. Keck Science Department, Claremont McKenna College, Claremont, CA, 91711, USA

    Luke A. Horton

  3. W.M. Keck Science Department, Scripps College, Claremont, CA, 91711, USA

    Madhuri P. Rao

  4. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, San Diego, CA, 92093, USA

    Kai H. Silkwood

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  1. Carl W. Decker
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  2. Joseph G. Casian
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  3. Kim Tho Nguyen
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Correspondence to Derick Han .

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  1. Department of Pharmacology Toxicology and Therapy, The University of Kansas Medical Center, Kansas City, Kansas, USA

    Wen-Xing Ding

  2. Health Pathology Laboratory, Indiana University, Indianapolis, Indiana, USA

    Xiao-Ming Yin

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Decker, C.W. et al. (2017). The Critical Role of Mitochondria in Drug-Induced Liver Injury. In: Ding, WX., Yin, XM. (eds) Molecules, Systems and Signaling in Liver Injury. Cell Death in Biology and Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-58106-4_8

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