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Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity

Authors :
Wen-Xing Ding
Abdellah Mansouri
Benjamin L. Woolbright
Kuo Du
Mitchell R. McGill
Hartmut Jaeschke
Anup Ramachandran
Tarik Asselah
Anwar Farhood
Source :
Food and Chemical Toxicology. 108:339-350
Publication Year :
2017
Publisher :
Elsevier BV, 2017.

Abstract

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.

Details

ISSN :
02786915
Volume :
108
Database :
OpenAIRE
Journal :
Food and Chemical Toxicology
Accession number :
edsair.doi.dedup.....cd1f460864d3ec3bf91a9e265a44e3cb