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The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury

Lucía Barbier-Torres1, Paula Iruzubieta1,2, David Fernández-Ramos1

  • 1Liver Disease Laboratory and Liver Metabolism Laboratory, CIC bioGUNE, CIBERehd, Bizkaia Science and Technology Park, Derio, 48160, Bizkaia, Spain.

Nature Communications
|December 14, 2017
PubMed

Insights

Acetaminophen (APAP) overdose causes liver injury by disrupting mitochondrial function via MCJ. Inhibiting MCJ protects the liver, offering a potential new therapy for APAP-induced liver damage.

Area of Science:

  • Hepatology
  • Mitochondrial Biology
  • Toxicology

Background:

  • Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide.
  • Mitochondrial dysfunction is implicated in APAP-induced liver injury, but mechanisms remain unclear.
  • Current therapies like N-acetylcysteine are not always effective.

Purpose of the Study:

  • To elucidate the mechanism of APAP-induced hepatotoxicity.
  • To identify novel therapeutic targets for APAP-induced liver injury.
  • To evaluate the role of mitochondrial protein MCJ in APAP toxicity.

Main Methods:

  • Investigated APAP's effect on mitochondrial respiratory supercomplexes in vitro and in vivo.
  • Utilized MCJ inhibitors in animal models of APAP overdose.
  • Analyzed MCJ levels in liver samples from patients with acetaminophen overdose.

Main Results:

  • APAP disrupts mitochondrial respiratory supercomplex formation by interacting with MCJ.
  • This disruption leads to reduced ATP production and increased reactive oxygen species (ROS) generation.
  • Inhibition of MCJ protected against APAP-induced liver injury, outperforming N-acetylcysteine.
  • Elevated MCJ levels were observed in human acetaminophen overdose cases.

Conclusions:

  • MCJ plays a critical role in APAP-induced hepatotoxicity.
  • Targeting MCJ represents a promising therapeutic strategy for acetaminophen overdose.
  • MCJ inhibition offers a potential alternative or adjunct therapy for liver injury prevention and treatment.

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