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Pro-oxidant effect of ALA is implicated in mitochondrial dysfunction of HepG2 cells.
MedLine Citation:
PMID:  25220386     Owner:  NLM     Status:  Publisher    
Heme biosynthesis begins in the mitochondrion with the formation of delta-aminolevulinic acid (ALA). In acute intermittent porphyria, hereditary tyrosinemia type I and lead poisoning patients, ALA is accumulated in plasma and in organs, especially the liver. These diseases are also associated with neuromuscular dysfunction and increased incidence of hepatocellular carcinoma. Many studies suggest that this damage may originate from ALA-induced oxidative stress following its accumulation. Using the MnSOD as an oxidative stress marker, we showed here that ALA treatment of cultured cells induced ROS production, increasing with ALA concentration. The mitochondrial energetic function of ALA-treated HepG2 cells was further explored. Mitochondrial respiration and ATP content were reduced compared to control cells. For the 300μM treatment, ALA induced a mitochondrial mass decrease and a mitochondrial network imbalance although neither necrosis nor apoptosis were observed. The up regulation of PGC-1, Tfam and ND5 genes was also found; these genes encode mitochondrial proteins involved in mitochondrial biogenesis activation and OXPHOS function. We propose that ALA may constitute an internal bioenergetic signal, which initiates a coordinated upregulation of respiratory genes, which ultimately drives mitochondrial metabolic adaptation within cells. The addition of an antioxidant, Manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), resulted in improvement of maximal respiratory chain capacity with 300μM ALA. Our results suggest that mitochondria, an ALA-production site, are more sensitive to pro-oxidant effect of ALA, and may be directly involved in pathophysiology of patients with inherited or acquired porphyria.
Jihane Laafi; Chadi Homedan; Caroline Jacques; Naig Gueguen; Caroline Schmitt; Hervé Puy; Pascal Reynier; M Carmen Martinez; Yves Malthiery
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-9-8
Journal Detail:
Title:  Biochimie     Volume:  -     ISSN:  1638-6183     ISO Abbreviation:  Biochimie     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1264604     Medline TA:  Biochimie     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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