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Low Dose Acetaminophen Induces Reversible Mitochondrial Dysfunction Associated with Transient c-Jun N-Terminal Kinase

Jiangting Hu1, Venkat K Ramshesh2, Mitchell R McGill3

  • 1*Center for Cell Death, Injury & Regeneration; Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology;

Toxicological Sciences : an Official Journal of the Society of Toxicology
|January 2, 2016
PubMed

Insights

Even nontoxic acetaminophen doses can cause reversible mitochondrial dysfunction and liver fat accumulation. High doses lead to irreversible damage and cell death via sustained JNK activation.

Area of Science:

  • Hepatology
  • Mitochondrial Biology
  • Toxicology

Background:

  • Acetaminophen (APAP) overdose is a leading cause of acute liver failure.
  • APAP-induced hepatotoxicity involves mitochondrial dysfunction and c-jun N-terminal kinase (JNK) activation.
  • The safe dosing limits of APAP remain controversial, necessitating further investigation into its effects at lower doses.

Purpose of the Study:

  • To investigate the role of mitochondrial permeability transition (MPT) and JNK activation in mitochondrial dysfunction following APAP administration.
  • To evaluate the effects of APAP doses considered nontoxic based on serum alanine aminotransferase (ALT) release and histological necrosis.
  • To assess the potential for sub-toxic APAP doses to induce reversible liver injury and steatosis.

Main Methods:

  • C57BL/6 mice were administered APAP at high (300 mg/kg) and low (150 mg/kg) doses.
  • Mice received APAP with or without MPT inhibitor (NIM811) or JNK inhibitor (SP600125).
  • Intravital multiphoton microscopy monitored in vivo cell viability, mitochondrial function, and fat droplet formation; serum ALT, liver histology, and JNK activation were also assessed.

Main Results:

  • High APAP dose induced ALT release, necrosis, irreversible mitochondrial dysfunction, and cell death.
  • Low APAP dose caused reversible mitochondrial dysfunction and hepatocyte steatosis without ALT release or necrosis.
  • MPT inhibition prevented APAP-induced cell death and mitochondrial depolarization; JNK inhibition partially reduced mitochondrial depolarization at low APAP doses.

Conclusions:

  • Low-dose APAP induces reversible, MPT-dependent mitochondrial dysfunction and steatosis in hepatocytes.
  • High-dose APAP leads to irreversible mitochondrial dysfunction and cell death associated with sustained JNK activation.
  • Sub-toxic APAP doses can cause transient mitochondrial dysfunction, potentially synergizing with other stressors to promote liver damage and steatosis.
Keywords:
APAPhepatocytesmitochondriamultiphoton microscopynontoxic dose

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