Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Du, K; Ramachandran, A; McGill, MR; Mansouri, A; Asselah, T; Farhood, A; Woolbright, BL; Ding, W-X; Jaeschke, H

Published Date

  • October 2017

Published In

Volume / Issue

  • 108 / Pt A

Start / End Page

  • 339 - 350

PubMed ID

  • 28827156

Pubmed Central ID

  • PMC5584682

Electronic International Standard Serial Number (EISSN)

  • 1873-6351

Digital Object Identifier (DOI)

  • 10.1016/j.fct.2017.08.020


  • eng

Conference Location

  • England