Transcriptional Regulation of SDHa flavoprotein by nuclear respiratory factor-1 prevents pseudo-hypoxia in aerobic cardiac cells.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Piantadosi, CA; Suliman, HB

Published Date

  • April 2008

Published In

Volume / Issue

  • 283 / 16

Start / End Page

  • 10967 - 10977

PubMed ID

  • 18252725

Pubmed Central ID

  • 18252725

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M709741200

Language

  • eng