Interaction of OKL38 and p53 in regulating mitochondrial structure and function

PLoS One. 2012;7(8):e43362. doi: 10.1371/journal.pone.0043362. Epub 2012 Aug 17.

Abstract

The tumor suppressor p53 is a well-known transcription factor controlling the expression of its target genes involved in cell cycle and apoptosis. In addition, p53 also plays a direct proapoptotic role in mitochondria by regulating cytochrome c release. Recently, we identified a novel downstream target of p53, OKL38, which relocalizes from nucleus to mitochondria upon forced expression to induce apoptosis. However, the mechanism underlying OKL38 targeting to mitochondria and apoptosis induction remains unclear. Here, we found that OKL38 interacts with p53 to regulate mitochondria function. After DNA damage, OKL38 colocalizes with p53 to mitochondria in U2OS cells. Further, p53 and OKL38 are targeted to mitochondria in synergy: forced expression of OKL38 leads to p53 localization to mitochondria while the expression of a mitochondria enriched p53 polymorphic variant, p53(R72), leads to OKL38 enrichment in mitochondria. Biochemical analyses found that OKL38 and p53 interact in vivo and in vitro via multiple domains. In cell biological assays, multiple regions of OKL38 mediate its mitochondria localization and induce mitochondria morphology changes. OKL38 induces formation of megamitochondria and increases cellular levels of reactive oxygen species. Furthermore, OKL38 induces cytochrome c release upon incubation with mitochondria. Taken together, our studies suggest that OKL38 regulates mitochondria morphology and functions during apoptosis together with p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • Cytochromes c / metabolism*
  • DNA Damage
  • Genetic Variation
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism*
  • Mitochondria / physiology
  • Mitochondria / ultrastructure
  • Protein Binding
  • Proteins / genetics
  • Proteins / metabolism*
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • OSGIN1 protein, human
  • Proteins
  • Reactive Oxygen Species
  • Tumor Suppressor Protein p53
  • Green Fluorescent Proteins
  • Cytochromes c