The Molecular Mechanism of Noxa-induced Mitochondrial Dysfunction in p53-Mediated Cell Death

Young Woo Seo, Jin Na Shin, Kang Hee Ko, Jong Hee Cha, Jae Yoon Park, Byoung Rai Lee, Cheol Won Yun, Young Myeong Kim, Dai Wu Seol, Dong Wook Kim, Xiao Ming Yin, Tae Hyoung Kim

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)

Abstract

Genotoxic stresses stabilize the p53 tumor suppressor protein which, in turn, transactivates target genes to cause apoptosis. Although Noxa, a "BH3-only" member of the Bcl-2 family, was shown to be a target of p53-mediated transactivation and to function as a mediator of p53-dependent apoptosis through mitochondrial dysfunction, the molecular mechanism by which Noxa causes mitochondrial dysfunction is largely unknown. Here we show that two domains (BH3 domain and mitochondrial targeting domain) in Noxa are essential for the release of cytochrome c from mitochondria. Noxa-induced cytochrome c release is inhibited by permeability transition pore inhibitors such as CsA or MgCl2, and Noxa induces an ultra-structural change of mitochondria yielding "swollen" mitochondria that are unlike changes induced by tBid. This indicates that Noxa may activate the permeability transition-related pore to release cytochrome c from mitochondria into cytosol. Moreover, Bak-oligomerization, which is an essential event for tBid-induced cytochrome c release in the extrinsic death signaling pathway, is not associated with Noxa-induced cytochrome c release. This finding suggests that the pathway of Noxa-induced mitochondrial dysfunction is distinct from the one of tBid-induced mitochondrial dysfunction. Thus, we propose that there are at least two different pathways of mitochondrial dysfunction; one mediated through Noxa in response to genotoxic stresses and the other through tBid in response to death ligands.

Original languageEnglish
Pages (from-to)48292-48299
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number48
DOIs
Publication statusPublished - 2003 Nov 28

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'The Molecular Mechanism of Noxa-induced Mitochondrial Dysfunction in p53-Mediated Cell Death'. Together they form a unique fingerprint.

Cite this