The mitochondrial protein NLRX1 controls the balance between extrinsic and intrinsic apoptosis

J Biol Chem. 2014 Jul 11;289(28):19317-30. doi: 10.1074/jbc.M114.550111. Epub 2014 May 27.


NLRX1 is a mitochondrial Nod-like receptor (NLR) protein whose function remains enigmatic. Here, we observed that NLRX1 expression was glucose-regulated and blunted by SV40 transformation. In transformed but not primary murine embryonic fibroblasts, NLRX1 expression mediated resistance to an extrinsic apoptotic signal, whereas conferring susceptibility to intrinsic apoptotic signals, such as glycolysis inhibition, increased cytosolic calcium and endoplasmic reticulum stress. In a murine model of colorectal cancer induced by azoxymethane, NLRX1-/- mice developed fewer tumors than wild type mice. In contrast, in a colitis-associated cancer model combining azoxymethane and dextran sulfate sodium, NLRX1-/- mice developed a more severe pathology likely due to the increased sensitivity to dextran sulfate sodium colitis. Together, these results identify NLRX1 as a critical mitochondrial protein implicated in the regulation of apoptosis in cancer cells. The unique capacity of NLRX1 to regulate the cellular sensitivity toward intrinsic versus extrinsic apoptotic signals suggests a critical role for this protein in numerous physiological processes and pathological conditions.

Keywords: Apoptosis; Carcinogenesis; Cell Death; Colon Cancer; Innate Immunity; Mitochondria; NLRs; Nod-like Receptor (NLR); Transformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line, Transformed
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / metabolism*
  • Colitis / pathology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Dextran Sulfate / toxicity
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*


  • Mitochondrial Proteins
  • NLRX1 protein, mouse
  • Neoplasm Proteins
  • Dextran Sulfate