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Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice.

Publication ,  Journal Article
Suliman, HB; Babiker, A; Withers, CM; Sweeney, TE; Carraway, MS; Tatro, LG; Bartz, RR; Welty-Wolf, KE; Piantadosi, CA
Published in: Free Radic Biol Med
March 1, 2010

Nitric oxide synthase-2 (NOS2) plays a critical role in reactive nitrogen species generation and cysteine modifications that influence mitochondrial function and signaling during inflammation. Here, we investigated the role of NOS2 in hepatic mitochondrial biogenesis during Escherichia coli peritonitis in mice. NOS2(-/-) mice displayed smaller mitochondrial biogenesis responses than Wt mice during E. coli infection according to differences in mRNA levels for the PGC-1 alpha coactivator, nuclear respiratory factor-1, mitochondrial transcription factor-A (Tfam), and mtDNA polymerase (Pol gamma). NOS2(-/-) mice did not significantly increase mitochondrial Tfam and Pol gamma protein levels during infection in conjunction with impaired mitochondrial DNA (mtDNA) transcription, loss of mtDNA copy number, and lower State 3 respiration rates. NOS2 blockade in mitochondrial-GFP reporter mice disrupted Hsp60 localization to mitochondria after E. coli exposure. Mechanistically, biotin-switch and immunoprecipitation studies demonstrated NOS2 binding to and S-nitros(yl)ation of Hsp60 and Hsp70. Specifically, NOS2 promoted Tfam accumulation in mitochondria by regulation of Hsp60-Tfam binding via S-nitros(yl)ation. In hepatocytes, site-directed mutagenesis identified (237)Cys as a critical residue for Hsp60 S-nitros(yl)ation. Thus, the role of NOS2 in inflammation-induced mitochondrial biogenesis involves both optimal gene expression for nuclear-encoded mtDNA-binding proteins and functional regulation of the Hsp60 chaperone that enables their importation for mtDNA transcription and replication.

Duke Scholars

Published In

Free Radic Biol Med

DOI

EISSN

1873-4596

Publication Date

March 1, 2010

Volume

48

Issue

5

Start / End Page

736 / 746

Location

United States

Related Subject Headings

  • Transcription Factors
  • Trans-Activators
  • Respiratory Rate
  • Protein Transport
  • Protein Binding
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Peritonitis
  • Nuclear Respiratory Factor 1
  • Nitric Oxide Synthase Type II
  • Mutagenesis, Site-Directed
 

Citation

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Suliman, H. B., Babiker, A., Withers, C. M., Sweeney, T. E., Carraway, M. S., Tatro, L. G., … Piantadosi, C. A. (2010). Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice. Free Radic Biol Med, 48(5), 736–746. https://doi.org/10.1016/j.freeradbiomed.2009.12.019
Suliman, Hagir B., Abdelwahid Babiker, Crystal M. Withers, Timothy E. Sweeney, Martha S. Carraway, Lynn G. Tatro, Raquel R. Bartz, Karen E. Welty-Wolf, and Claude A. Piantadosi. “Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice.Free Radic Biol Med 48, no. 5 (March 1, 2010): 736–46. https://doi.org/10.1016/j.freeradbiomed.2009.12.019.
Suliman HB, Babiker A, Withers CM, Sweeney TE, Carraway MS, Tatro LG, et al. Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice. Free Radic Biol Med. 2010 Mar 1;48(5):736–46.
Suliman, Hagir B., et al. “Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice.Free Radic Biol Med, vol. 48, no. 5, Mar. 2010, pp. 736–46. Pubmed, doi:10.1016/j.freeradbiomed.2009.12.019.
Suliman HB, Babiker A, Withers CM, Sweeney TE, Carraway MS, Tatro LG, Bartz RR, Welty-Wolf KE, Piantadosi CA. Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice. Free Radic Biol Med. 2010 Mar 1;48(5):736–746.
Journal cover image

Published In

Free Radic Biol Med

DOI

EISSN

1873-4596

Publication Date

March 1, 2010

Volume

48

Issue

5

Start / End Page

736 / 746

Location

United States

Related Subject Headings

  • Transcription Factors
  • Trans-Activators
  • Respiratory Rate
  • Protein Transport
  • Protein Binding
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Peritonitis
  • Nuclear Respiratory Factor 1
  • Nitric Oxide Synthase Type II
  • Mutagenesis, Site-Directed