title: Mitochondrial translocation of Nur77 mediates cardiomyocyte apoptosis.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: San Diego State Heart Institute, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA.
authors.forename: Zhaokang
authors.initials: Z
authors.lastname: Cheng
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.forename: Natalie
authors.initials: N
authors.lastname: Gude
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.forename: Tao
authors.initials: T
authors.lastname: Bo
authors.forename: Silvia
authors.initials: S
authors.lastname: Truffa
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez
authors.forename: Matt
authors.initials: M
authors.lastname: Mason
authors.forename: Kimberlee M
authors.initials: KM
authors.lastname: Fischer
authors.forename: Mathias H
authors.initials: MH
authors.lastname: Konstandin
authors.forename: Xiao-kun
authors.initials: XK
authors.lastname: Zhang
authors.forename: Joan
authors.initials: J
authors.lastname: Heller Brown
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003250:Constriction; D005260:Female; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000502:physiology*; D017202:Myocardial Ischemia / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D015854:Up-Regulation
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1