Endoplasmic Reticulum Stress and Mitochondrial Stress in Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) is a widespread and harmful disease closely linked to mitochondrial and endoplasmic reticulum stress (ERS). Globally, severe drug-induced hepatitis, cirrhosis, and liver cancer are the primary causes of liver-related morbidity and mortality. A hallmark of DILI is ERS and changes in mitochondrial morphology and function, which increase the production of reactive oxygen species (ROS) in a vicious cycle of mutually reinforcing stress responses. Several pathways are maladapted to maintain homeostasis during DILI. Here, we discuss the processes of liver injury caused by several types of drugs that induce hepatocyte stress, focusing primarily on DILI by ERS and mitochondrial stress. Importantly, both ERS and mitochondrial stress are mediated by the overproduction of ROS, destruction of Ca²⁺ homeostasis, and unfolded protein response (UPR). Additionally, we review new pathways and potential pharmacological targets for DILI to highlight new possibilities for DILI treatment and mitigation.

Keywords: ERS; drug-induced liver injury; mitochondrial stress.

Figure 1

Mitochondrial stress and ERS in APAP and INH-induced liver injury. (APAP: Acetaminophen; NAPQI: N-acetyl-p-benzoquinone imine; ROS: Radical Oxygen Species; JNK: c-jun N-terminal kinase; MPT: Mitochondrial phosphate transporter; Bax: BCL2-Associated X; INH: Isoniazid; mit stress: Mitochondrial stress; mt DNA: Mitochondrial Deoxyribonucleic acid; GSH: Glutathione; ERS: Endoplasmic reticulum stress; TCA: Tricarboxylic acid).

Figure 2

SPHK1 pathway in liver injury. (SPHK1: sphingosine kinase-1; S1P: Sphingosine-1-phosphate; PERK: PKR-like ER kinase; IRE1α; Inositol-requiring enzyme-1α; CHOP: C/EBP-homologous Protein; ATF4: Activating Transcription Factor 4; ATF6: Activating Transcription Factor 6; ASK1: Apoptosis signal-regulating kinase 1; GSK3β: Glycogen Synthetase Kinase 3β; TRAF2: TNF receptor-associated factor 2; NF-κB: Nuclear Factor Kappa B).

Figure 3

ATF6 pathway. (S2P: Sphingosine-1-phosphate; ERSE: ERS-response element; BIP: binding protein; XBP1: X-box binding protein 1).

Figure 4

IRE1 pathway. (S2P: Sphingosine-1-phosphate; ERSE: ERS-response element; BIP: binding protein; XBP1: X-box binding protein 1).

Figure 5

PERK pathway.

Figure 6

Caspase-12 pathway.

Figure 7

Mitochondrial stress pathways.

Figure 8

Communication between the ERS and mitochondria stress (LONP1: Lon peptidase1; VDAC1: Voltage dependent anion channel protein 1; IP3R: Inositol 1,4,5 triphosphate receptor; MFN1: Mitofusin 1; MFN2: Mitofusin 2; Sig-1R: Sigma 1 receptor; DELE1: DAP3 binding cell death enhancer 1).