Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility

Research output: Contribution to journalArticle

Abstract

Mitochondria control bioenergetics and cell fate decisions, but how they influence nuclear gene expression is understood poorly. Here, we show that deletion or reduction in the levels of cyclophilin D (CypD, also called Ppif), a mitochondrial matrix peptidyl prolyl isomerase and apoptosis regulator, results in increased cell proliferation and enhanced cell migration and invasion. These responses are associated with extensive transcriptional changes, modulation of a chemokine/chemokine receptor gene signature, and activation of the pleiotropic inflammatory mediator, STAT3. In the absence of CypD, active STAT3 enhances cell proliferation via accelerated entry into S-phase and stimulates autocrine/paracrine cell motility through Cxcl12-Cxcr4-directed chemotaxis. Therefore, CypD directs mitochondria-to-nuclei inflammatory gene expression in normal and tumor cells. This pathway may contribute to malignant traits under conditions of CypD modulation.

Details

Authors
  • Michele Tavecchio
  • Sofia Lisanti
  • Aaron Lam
  • Jagadish C Ghosh
  • Nina M Martin
  • Michael O'Connell
  • Ashani T. Weeraratna
  • Andrew V Kossenkov
  • Louise C Showe
  • Dario C Altieri
External organisations
  • The Wistar Institute
Research areas and keywords

Keywords

  • Animals, Apoptosis, Cell Cycle, Cell Line, Tumor, Cell Lineage, Cell Movement, Cell Proliferation, Cell Survival, Chemokines, Cyclophilins, Gene Expression Profiling, Gene Expression Regulation, Gene Expression Regulation, Neoplastic, Humans, Mice, Mitochondria, NIH 3T3 Cells, RNA, Small Interfering, STAT3 Transcription Factor, Signal Transduction, Journal Article, Research Support, N.I.H., Extramural
Original languageEnglish
Pages (from-to)5553-61
Number of pages9
JournalJournal of Biological Chemistry
Volume288
Issue number8
Publication statusPublished - 2013 Feb 22
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes