PMID- 18252725
OWN - NLM
STAT- MEDLINE
DCOM- 20080610
LR  - 20211020
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 16
DP  - 2008 Apr 18
TI  - Transcriptional Regulation of SDHa flavoprotein by nuclear respiratory factor-1 
      prevents pseudo-hypoxia in aerobic cardiac cells.
PG  - 10967-77
LID - 10.1074/jbc.M709741200 [doi]
AB  - Nuclear respiratory factor-1 (NRF-1) is integral to the transcriptional 
      regulation of mitochondrial biogenesis, but its control over various respiratory 
      genes overlaps other regulatory elements including those involved in O(2) 
      sensing. Aerobic metabolism generally suppresses hypoxia-sensitive genes, e.g. 
      via hypoxia-inducible factor-1 (HIF-1), but mutations in Complex II-succinate 
      dehydrogenase (SDH), a tumor suppressor, stabilize HIF-1, producing 
      pseudo-hypoxia. In aerobic cardiomyocytes, which rely on oxidative 
      phosphorylation, we tested the hypothesis that NRF-1 regulates Complex II 
      expression and opposes hypoxia-inducible factor-1. NRF-1 gene silencing blocked 
      aerobic succinate oxidation, increasing nuclear HIF-1alpha protein prior to the 
      loss of Complex I function. We postulated that NRF-1 suppression either 
      specifically decreases the expression of one or more SDH subunits and increases 
      succinate availability to regulate HIF-1 prolyl hydroxylases, or stimulates 
      mitochondrial reactive oxygen production, which interferes with HIF-1alpha 
      degradation. Using promoter analysis, gene silencing, and chromatin 
      immunoprecipitation, NRF-1 was found to bind to the gene promoters of two of four 
      nuclear-encoded Complex II subunits: SDHa and SDHd, but the enzyme activity was 
      dynamically regulated through the catalytic SDHa flavoprotein. Complex II was 
      inactivated by SDHa silencing, which led to aerobic HIF-1alpha stabilization, 
      nuclear translocation, and enhanced expression of glucose transporters and heme 
      oxygenase-1. This was unrelated to mitochondrial ROS production, reversible by 
      high alpha-ketoglutarate concentrations, and coherent with regulation of HIF-1 by 
      succinate reported in tumor cells. These findings disclose a novel role for NRF-1 
      in the transcriptional control of Complex II and prevention of pseudo-hypoxic 
      gene expression in aerobic cardiac cells.
FAU - Piantadosi, Claude A
AU  - Piantadosi CA
AD  - Department of Medicine, Duke University School of Medicine and the Durham 
      Veteran's Administration Medical Center, Durham, North Carolina 27710, USA. 
      piant001@mc.duke.edu
FAU - Suliman, Hagir B
AU  - Suliman HB
LA  - eng
GR  - R01 HL090679/HL/NHLBI NIH HHS/United States
GR  - P01 42-444/PHS HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20080205
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Flavoproteins)
RN  - 0 (Nuclear Respiratory Factor 1)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.3.99.1 (Succinate Dehydrogenase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cell Nucleus/metabolism
MH  - Flavoproteins/*metabolism
MH  - *Gene Expression Regulation
MH  - Glucose/metabolism
MH  - Hypoxia
MH  - Mitochondria/metabolism
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Nuclear Respiratory Factor 1/*metabolism
MH  - Rats
MH  - Reactive Oxygen Species
MH  - Succinate Dehydrogenase/*chemistry
MH  - *Transcription, Genetic
PMC - PMC2447662
EDAT- 2008/02/07 09:00
MHDA- 2008/06/11 09:00
PMCR- 2009/04/18
CRDT- 2008/02/07 09:00
PHST- 2008/02/07 09:00 [pubmed]
PHST- 2008/06/11 09:00 [medline]
PHST- 2008/02/07 09:00 [entrez]
PHST- 2009/04/18 00:00 [pmc-release]
AID - S0021-9258(20)62064-6 [pii]
AID - 10967 [pii]
AID - 10.1074/jbc.M709741200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Apr 18;283(16):10967-77. doi: 10.1074/jbc.M709741200. Epub 2008 
      Feb 5.