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Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity.

Publication ,  Journal Article
Du, K; Ramachandran, A; McGill, MR; Mansouri, A; Asselah, T; Farhood, A; Woolbright, BL; Ding, W-X; Jaeschke, H
Published in: Food Chem Toxicol
October 2017

Mitochondrial biogenesis (MB) is an adaptive response to maintain metabolic homeostasis after mitochondrial dysfunction. Induction of MB during APAP hepatotoxicity has not been studied. To investigate this, mice were treated with toxic doses of APAP and euthanized between 0 and 96 h. At early time points, APAP caused both mitochondrial dysfunction and reduction of mitochondrial mass, indicated by reduced activity of electron transport chain (ETC) complexes I and IV and depletion of mitochondrial DNA (mtDNA), respectively. Both ETC activity and mtDNA gradually recovered after 12 h, suggesting that MB occurs at late time points after APAP overdose. Immunofluorescent staining of mitochondria with mitochondrial outer membrane protein Tom20 further demonstrated that MB occurs selectively in hepatocytes surrounding necrotic areas. MB signaling mediators including PPARγ co-activator 1-α (Pgc-1α), nuclear respiratory factor-1 (Nrf-1) and mitochondrial fission protein dynamin-related protein-1 (Drp-1) were induced. Pgc-1α was selectively increased in hepatocytes surrounding necrotic areas. In addition, the time course of MB induction coincides with increased liver regeneration. Post-treatment with the known MB inducer SRT1720 increased Pgc-1α expression and liver regeneration, resulting in protection against late liver injury after APAP overdose. Thus, induction of MB is an important feature during APAP hepatotoxicity and liver regeneration.

Duke Scholars

Published In

Food Chem Toxicol

DOI

EISSN

1873-6351

Publication Date

October 2017

Volume

108

Issue

Pt A

Start / End Page

339 / 350

Location

England

Related Subject Headings

  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Liver
  • Food Science
  • Electron Transport Chain Complex Proteins
  • Dose-Response Relationship, Drug
  • DNA, Mitochondrial
  • Chemical and Drug Induced Liver Injury
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Du, K., Ramachandran, A., McGill, M. R., Mansouri, A., Asselah, T., Farhood, A., … Jaeschke, H. (2017). Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food Chem Toxicol, 108(Pt A), 339–350. https://doi.org/10.1016/j.fct.2017.08.020
Du, Kuo, Anup Ramachandran, Mitchell R. McGill, Abdellah Mansouri, Tarik Asselah, Anwar Farhood, Benjamin L. Woolbright, Wen-Xing Ding, and Hartmut Jaeschke. “Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity.Food Chem Toxicol 108, no. Pt A (October 2017): 339–50. https://doi.org/10.1016/j.fct.2017.08.020.
Du K, Ramachandran A, McGill MR, Mansouri A, Asselah T, Farhood A, et al. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food Chem Toxicol. 2017 Oct;108(Pt A):339–50.
Du, Kuo, et al. “Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity.Food Chem Toxicol, vol. 108, no. Pt A, Oct. 2017, pp. 339–50. Pubmed, doi:10.1016/j.fct.2017.08.020.
Du K, Ramachandran A, McGill MR, Mansouri A, Asselah T, Farhood A, Woolbright BL, Ding W-X, Jaeschke H. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food Chem Toxicol. 2017 Oct;108(Pt A):339–350.
Journal cover image

Published In

Food Chem Toxicol

DOI

EISSN

1873-6351

Publication Date

October 2017

Volume

108

Issue

Pt A

Start / End Page

339 / 350

Location

England

Related Subject Headings

  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Liver
  • Food Science
  • Electron Transport Chain Complex Proteins
  • Dose-Response Relationship, Drug
  • DNA, Mitochondrial
  • Chemical and Drug Induced Liver Injury