ArticleArchives of toxicology2019
Mito-tempo protects against acute liver injury but induces limited secondary apoptosis during the late phase of acetaminophen hepatotoxicity.
Article in Archives of toxicology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 62 citations in OpenAlex.
- Loss of Vacuole Membrane Protein 1 protects against acetaminophen-induced liver injury by modulating inflammation and hepatocyte proliferation.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- CK2α Deficiency Drives Myocardial Fibrosis via Desmin-Induced Mitochondrial Dysfunction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Dose- and Organ-Specific Dual Effects of MitoTempo in Paracetamol-Induced Hepatorenal Toxicity in Mice.Biomolecules · 2026Article
- 2-Methoxystypandrone fromAntioxidants (Basel, Switzerland) · 2026Article
- Article
- Magnesium isoglycyrrhizinate prevented the liver injury of acetaminophen by promoting mitochondrial biogenesis.Toxicology research · 2025Article
- Targeted Modulation of Mitochondrial Oxidative Stress Ameliorates 5-Fluorouracil-Induced Renal Injury in BALB/c Mice.Oxidative medicine and cellular longevity · 2025Article
- The multiple mechanisms and modes of cell death after acetaminophen overdose.Exploration of digestive diseases · 2025Article
- LPI-GPR55 promotes endothelial cell activation and inhibits autophagy through inducing LINC01235 expression.Annals of medicine · 2024Article
- Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure.Biochemical pharmacology · 2024Review
- Drug-induced oxidative stress actively prevents caspase activation and hepatocyte apoptosis.Cell death & disease · 2024Article
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury.Annual review of pathology · 2024Review
- Mitochondrial Reactive Oxygen Species and Lytic Programmed Cell Death in Acute Inflammation.Antioxidants & redox signaling · 2023Review
- Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage.Neural regeneration research · 2023Article
- Attenuation of Sepsis-Induced Acute Kidney Injury by Exogenous HMolecules (Basel, Switzerland) · 2023Article
- Article
- A system that delivers an antioxidant to mitochondria for the treatment of drug-induced liver injury.Scientific reports · 2023Article
- Mitigation of acetaminophen-induced liver toxicity by the novel phosphatidylinositol 3-kinase inhibitor alpelisib.Frontiers in pharmacology · 2023Article
- Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
We previously reported that delayed treatment with Mito-tempo (MT), a mitochondria-targeted superoxide dismutase mimetic, protects against the early phase of acetaminophen (APAP) hepatotoxicity by inhibiting peroxynitrite formation. However, whether this protection is sustained to the late phase of toxicity is unknown. To investigate the late protection, C57Bl/6J mice were treated with 300 mg/kg APAP followed by 20 mg/kg MT 1.5 h or 3 h later. We found that both MT treatments protected against the late phase of APAP hepatotoxicity at 12 and 24 h. Surprisingly, MT-treated mice demonstrated a significant increase in apoptotic hepatocytes, while the necrotic phenotype was observed almost exclusively in mice treated with APAP alone. In addition, there was a significant increase in caspase-3 activity and cleavage in the livers of MT-treated mice. Immunostaining for active caspase-3 revealed that the positively stained hepatocytes were exclusively in centrilobular areas. Treatment with the pan-caspase inhibitor ZVD-fmk (10 mg/kg) 2 h post-APAP neutralized this caspase activation and provided additional protection against APAP hepatotoxicity. Treatment with N-acetylcysteine, the current standard of care for APAP poisoning, protected but did not induce this apoptotic phenotype. Mechanistically, MT treatment inhibited APAP-induced RIP3 kinase expression, and RIP3-deficient mice showed caspase activation and apoptotic morphology in hepatocytes analogous to MT treatment. These data suggest that while necrosis is the primary cause of cell death after APAP hepatotoxicity, treatment with the antioxidant MT may switch the mode of cell death to secondary apoptosis in some cells. Modulation of mitochondrial oxidative stress and RIP3 kinase expression play critical roles in this switch.
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