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Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity
- 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.
- Subjects :
- Male
0301 basic medicine
Mitochondrion
Biology
Toxicology
DNA, Mitochondrial
Article
Mice
03 medical and health sciences
DNM1L
0302 clinical medicine
medicine
Animals
NRF1
Acetaminophen
Liver injury
Dose-Response Relationship, Drug
digestive, oral, and skin physiology
General Medicine
Analgesics, Non-Narcotic
medicine.disease
Molecular biology
Liver regeneration
Mitochondria
Mice, Inbred C57BL
030104 developmental biology
Electron Transport Chain Complex Proteins
Liver
Mitochondrial biogenesis
Biochemistry
Mitochondrial permeability transition pore
030220 oncology & carcinogenesis
Mitochondrial fission
Chemical and Drug Induced Liver Injury
Food Science
Subjects
Details
- ISSN :
- 02786915
- Volume :
- 108
- Database :
- OpenAIRE
- Journal :
- Food and Chemical Toxicology
- Accession number :
- edsair.doi.dedup.....cd1f460864d3ec3bf91a9e265a44e3cb