Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosis.

AIMS The cascade of events leading to compromised mitochondrial integrity in response to stress is mediated by various combinatorial interactions of pro- and anti-apoptotic molecules. Nur77, an immediate early gene that encodes a nuclear orphan receptor, translocates from the nucleus to mitochondria to induce cytochrome c release and apoptosis in cancer cells in response to various pro-apoptotic treatments. However, the role of Nur77 in the cardiac setting is still unclear. The objective of this study is to determine the physiological relevance and pathophysiological importance of Nur77 in cardiomyocytes. METHODS AND RESULTS Myocardial Nur77 is upregulated following cardiomyopathic injury and, while expressed in the postnatal myocardium, declines in level within weeks after birth. Nur77 is localized predominantly in cardiomyocyte nuclei under normal conditions where it is not apoptotic, but translocates to mitochondria in response to oxidative stress both in vitro and in vivo. Mitochondrial localization of Nur77 induces cytochrome c release and typical morphological features of apoptosis, including chromatin condensation and DNA fragmentation. Knockdown of Nur77 rescued hydrogen peroxide-induced cardiomyocyte apoptosis. CONCLUSION Translocation of Nur77 from the nucleus to the mitochondria in cardiomyocytes results in the loss of mitochondrial integrity and subsequent apoptosis in response to ischaemia/reperfusion injury. Our findings identify Nur77 as a novel mediator of cardiomyocyte apoptosis and warrants further investigation of mitochondrial Nur77 translocation as a mechanism to control cell death in the treatment of ischaemic heart diseases.

[1]  Hyun-Jin Kang,et al.  Regulation of Nur77 protein turnover through acetylation and deacetylation induced by p300 and HDAC1. , 2010, Biochemical pharmacology.

[2]  A. Winoto,et al.  Protein kinase C regulates mitochondrial targeting of Nur77 and its family member Nor‐1 in thymocytes undergoing apoptosis , 2010, European journal of immunology.

[3]  Hueng-Sik Choi,et al.  Involvement of induction and mitochondrial targeting of orphan nuclear receptor Nur77 in 6-OHDA-induced SH-SY5Y cell death , 2010, Neurochemistry International.

[4]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2010 update: a report from the American Heart Association. , 2010, Circulation.

[5]  P. Pasdois,et al.  The role of the mitochondrial permeability transition pore in heart disease. , 2009, Biochimica et biophysica acta.

[6]  Mark A Sussman,et al.  Cardioprotective stimuli mediate phosphoinositide 3-kinase and phosphoinositide dependent kinase 1 nuclear accumulation in cardiomyocytes. , 2009, Journal of molecular and cellular cardiology.

[7]  Xue Leng,et al.  NGFI-B targets mitochondria and induces cardiomyocyte apoptosis in restraint-stressed rats by mediating energy metabolism disorder , 2009, Cell Stress and Chaperones.

[8]  S. Mutka,et al.  Identification of nuclear export inhibitors with potent anticancer activity in vivo. , 2009, Cancer research.

[9]  Yu Cao,et al.  Modulation of orphan nuclear receptor Nur77-mediated apoptotic pathway by acetylshikonin and analogues. , 2008, Cancer research.

[10]  John Calvin Reed,et al.  A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. , 2008, Cancer cell.

[11]  H. Harn,et al.  The Induction of Orphan Nuclear Receptor Nur77 Expression by n-Butylenephthalide as Pharmaceuticals on Hepatocellular Carcinoma Cell Therapy , 2008, Molecular Pharmacology.

[12]  A. Winoto,et al.  During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain , 2008, The Journal of experimental medicine.

[13]  D. Yellon,et al.  Myocardial reperfusion injury. , 2007, The New England journal of medicine.

[14]  Zidong Zhang,et al.  Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle. , 2007, Molecular endocrinology.

[15]  S. Hamilton,et al.  Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and nuclear receptor-independent pathways. , 2007, Cancer research.

[16]  T. Osumi,et al.  Orphan nuclear receptor Nur77 accelerates the initial phase of adipocyte differentiation in 3T3-L1 cells by promoting mitotic clonal expansion. , 2006, Journal of biochemistry.

[17]  S. Houser,et al.  Pim-1 regulates cardiomyocyte survival downstream of Akt , 2006, Nature Medicine.

[18]  U. Moll,et al.  p53 and Nur77/TR3 – transcription factors that directly target mitochondria for cell death induction , 2006, Oncogene.

[19]  John Calvin Reed,et al.  Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt , 2006, Oncogene.

[20]  P. Bernardi,et al.  Mitochondria and ischemia-reperfusion injury of the heart: fixing a hole. , 2006, Cardiovascular research.

[21]  P. Tontonoz,et al.  Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77. , 2006, Molecular endocrinology.

[22]  Horst Kessler,et al.  WT p53, but Not Tumor-derived Mutants, Bind to Bcl2 via the DNA Binding Domain and Induce Mitochondrial Permeabilization* , 2006, Journal of Biological Chemistry.

[23]  E. Manseau,et al.  The Journal of Experimental Medicine CORRESPONDENCE , 2005 .

[24]  G. Cooney,et al.  Nur77 Regulates Lipolysis in Skeletal Muscle Cells , 2005, Journal of Biological Chemistry.

[25]  R. Paulsen,et al.  ERK2 Prohibits Apoptosis-induced Subcellular Translocation of Orphan Nuclear Receptor NGFI-B/TR3* , 2004, Journal of Biological Chemistry.

[26]  P. Doevendans,et al.  MEK1-ERK2 Signaling Pathway Protects Myocardium From Ischemic Injury In Vivo , 2004, Circulation.

[27]  John Calvin Reed,et al.  Conversion of Bcl-2 from Protector to Killer by Interaction with Nuclear Orphan Receptor Nur77/TR3 , 2004, Cell.

[28]  Martin Schuler,et al.  Direct Activation of Bax by p53 Mediates Mitochondrial Membrane Permeabilization and Apoptosis , 2004, Science.

[29]  A. Rajpal,et al.  Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor , 2003, The EMBO journal.

[30]  T. Mak,et al.  Nur77 as a survival factor in tumor necrosis factor signaling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Qiao Wu,et al.  Dual roles of Nur77 in selective regulation of apoptosis and cell cycle by TPA and ATRA in gastric cancer cells. , 2002, Carcinogenesis.

[32]  R. Paulsen,et al.  Nuclear receptor and apoptosis initiator NGFI-B is a substrate for kinase ERK2. , 2002, Biochemical and biophysical research communications.

[33]  Y. Pekarsky,et al.  Akt phosphorylates and regulates the orphan nuclear receptor Nur77 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  John Calvin Reed,et al.  Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. , 2000, Science.

[35]  V. Ferrans,et al.  Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B , 2000, Nature Cell Biology.

[36]  C. Thompson,et al.  Bcl-2-family proteins: the role of the BH3 domain in apoptosis. , 1998, Trends in cell biology.

[37]  Minoru Yoshida,et al.  CRM1 Is an Export Receptor for Leucine-Rich Nuclear Export Signals , 1997, Cell.

[38]  B. Calnan,et al.  Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis , 1995, Molecular and cellular biology.

[39]  G. Linette,et al.  Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). , 1995, Science.

[40]  L. Schwartz,et al.  Apoptotic signals delivered through the T-cell receptor of a T-cell hybrid require the immediate–early gene nur77 , 1994, Nature.

[41]  B. Calnan,et al.  Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas , 1994, Nature.