PMID- 23316324
OWN - NLM
STAT- MEDLINE
DCOM- 20130808
LR  - 20220317
IS  - 2047-9980 (Electronic)
IS  - 2047-9980 (Linking)
VI  - 1
IP  - 6
DP  - 2012 Dec
TI  - Defects of mtDNA replication impaired mitochondrial biogenesis during Trypanosoma 
      cruzi infection in human cardiomyocytes and chagasic patients: the role of Nrf1/2 
      and antioxidant response.
PG  - e003855
LID - 10.1161/JAHA.112.003855 [doi]
LID - e003855
AB  - BACKGROUND: Mitochondrial dysfunction is a key determinant in chagasic 
      cardiomyopathy development in mice; however, its relevance in human Chagas 
      disease is not known. We determined if defects in mitochondrial biogenesis and 
      dysregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) 
      coactivator-1 (PGC-1)-regulated transcriptional pathways constitute a mechanism 
      or mechanisms underlying mitochondrial oxidative-phosphorylation (OXPHOS) 
      deficiency in human Chagas disease. METHODS AND RESULTS: We utilized human 
      cardiomyocytes and left-ventricular tissue from chagasic and other cardiomyopathy 
      patients and healthy donors (n>6/group). We noted no change in citrate synthase 
      activity, yet mRNA and/or protein levels of subunits of the respiratory complexes 
      were significantly decreased in Trypanosoma cruzi-infected cardiomyocytes (0 to 
      24 hours) and chagasic hearts. We observed increased mRNA and decreased nuclear 
      localization of PGC-1-coactivated transcription factors, yet the expression of 
      genes for PPARgamma-regulated fatty acid oxidation and nuclear respiratory factor 
      (NRF1/2)-regulated mtDNA replication and transcription machinery was enhanced in 
      infected cardiomyocytes and chagasic hearts. The D-loop formation was normal or 
      higher, but mtDNA replication and mtDNA content were decreased by 83% and 40% to 
      65%, respectively. Subsequently, we noted that reactive oxygen species (ROS), 
      oxidative stress, and mtDNA oxidation were significantly increased, yet 
      NRF1/2-regulated antioxidant gene expression remained compromised in infected 
      cardiomyocytes and chagasic hearts. CONCLUSIONS: The replication of mtDNA was 
      severely compromised, resulting in a significant loss of mtDNA and expression of 
      OXPHOS genes in T cruzi-infected cardiomyocytes and chagasic hearts. Our data 
      suggest increased ROS generation and selective functional incapacity of 
      NRF2-mediated antioxidant gene expression played a role in the defects in mtDNA 
      replication and unfitness of mtDNA for replication and gene expression in Chagas 
      disease.
FAU - Wan, Xianxiu
AU  - Wan X
AD  - Department of Microbiology and Immunology, University of Texas Medical Branch, 
      Galveston, TX 77555-1070, USA.
FAU - Gupta, Shivali
AU  - Gupta S
FAU - Zago, Maria P
AU  - Zago MP
FAU - Davidson, Mercy M
AU  - Davidson MM
FAU - Dousset, Pierre
AU  - Dousset P
FAU - Amoroso, Alejandro
AU  - Amoroso A
FAU - Garg, Nisha Jain
AU  - Garg NJ
LA  - eng
GR  - R01 AI054578/AI/NIAID NIH HHS/United States
GR  - R01 HL094802/HL/NHLBI NIH HHS/United States
GR  - HL094802/HL/NHLBI NIH HHS/United States
GR  - AI054578/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20121219
PL  - England
TA  - J Am Heart Assoc
JT  - Journal of the American Heart Association
JID - 101580524
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (NRF1 protein, human)
RN  - 0 (Nuclear Respiratory Factor 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Transcription Factors)
RN  - 0 (peroxisome-proliferator-activated receptor-gamma coactivator-1)
SB  - IM
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Chagas Disease/genetics/metabolism/*physiopathology
MH  - DNA Replication/*physiology
MH  - DNA, Mitochondrial/metabolism/*physiology
MH  - Gene Expression Regulation
MH  - Humans
MH  - Immunohistochemistry
MH  - Microscopy, Fluorescence
MH  - Mitochondrial Diseases/genetics/physiopathology
MH  - Mitochondrial Turnover/*physiology
MH  - Myocytes, Cardiac/physiology/ultrastructure
MH  - NF-E2-Related Factor 2/genetics/metabolism/physiology
MH  - Nuclear Respiratory Factor 1/genetics/metabolism/physiology
MH  - RNA, Messenger/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Transcription Factors/genetics/metabolism/physiology
MH  - *Trypanosoma cruzi
PMC - PMC3540675
OTO - NOTNLM
OT  - Chagas disease
OT  - NRF2
OT  - PGC-1alpha
OT  - Trypanosoma cruzi
OT  - mitochondrial biogenesis
OT  - mtDNA replication
OT  - oxidative stress
EDAT- 2013/01/15 06:00
MHDA- 2013/08/09 06:00
PMCR- 2012/12/01
CRDT- 2013/01/15 06:00
PHST- 2012/08/16 00:00 [received]
PHST- 2012/10/09 00:00 [accepted]
PHST- 2013/01/15 06:00 [entrez]
PHST- 2013/01/15 06:00 [pubmed]
PHST- 2013/08/09 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - jah3110 [pii]
AID - 10.1161/JAHA.112.003855 [doi]
PST - ppublish
SO  - J Am Heart Assoc. 2012 Dec;1(6):e003855. doi: 10.1161/JAHA.112.003855. Epub 2012 
      Dec 19.