BGP-15 Protects Mitochondria in Acute, Acetaminophen Overdose Induced Liver Injury

Farkas Sarnyai,József Mandl,Timea Szekerczés,Miklós Csala,András Szarka,Zsuzsa Schaff,Balázs Sümegi

doi:10.1007/s12253-019-00721-1

Abstract

Acetaminophen (APAP) induced hepatotoxicity involves activation of c-Jun amino-terminal kinase (JNK), mitochondrial damage and ER stress. BGP-15, a hydroximic acid derivative, has been reported to have hepatoprotective effects in APAP overdose induced liver damage. Effect of BGP-15 was further investigated on mitochondria in APAP-overdose induced acute liver injury in mice. We found that BGP-15 efficiently preserved mitochondrial morphology, and it caused a marked decrease in the number of damaged mitochondria. Attenuation of mitochondrial damage by BGP-15 is supported by immunohistochemistry as the TOMM20 label and the co-localized autophagy markers detected in the livers of APAP-treated mice were markedly reduced upon BGP-15 administration. This effect, along with the observed prevention of JNK activation likely contribute to the mitochondrial protective action of BGP-15.

Highlights

Acetaminophen (N-acetyl-p-aminophenol, APAP) is the most common painkiller, antifebrile and one of the most frequently used drugs in the world [1]
Nuclear translocation of AIF and endonuclease G from the mitochondria is a well-known event of caspase-independent apoptosis, and it was demonstrated in livers of APAPtreated animals [5, 17]
(Fig. 3b) livers were more like those of the control animals (Fig. 3c) and only very few brown granules were observed in the APAP+BGP15-treated livers (Fig. 3d)

Summary

Introduction

Acetaminophen (N-acetyl-p-aminophenol, APAP) is the most common painkiller, antifebrile and one of the most frequently used drugs in the world [1]. APAP is a dosedependent hepatotoxin, with approximately 50% of all acute liver failure cases in the USA and UK attributed to APAP overdose [2]. The toxicity of APAP is a complicated process and it is not fully understood. Several organelles and Farkas Sarnyai and Timea Szekerczés contributed to this work. 2 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest H-1091, Hungary pathomechanism of APAP toxicity [15]. JNK amplifies the already existing mitochondrial oxidant stress and largely contributes to cell death by stimulating MOMP (mitochondrial outer membrane permeabilization) and MPT (mitochondrial permeability transition) [16], which leads to the collapse of mitochondrial membrane potential and to the release of various proapoptotic mediators. Nuclear translocation of AIF (apoptosis-inducing factor) and endonuclease G from the mitochondria is a well-known event of caspase-independent apoptosis, and it was demonstrated in livers of APAPtreated animals [5, 17]

Methods

Results

Conclusion