title: Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility.
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.
authors.affiliation: Prostate Cancer Discovery and Development Program, Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Tavecchio
authors.forename: Sofia
authors.initials: S
authors.lastname: Lisanti
authors.forename: Aaron
authors.initials: A
authors.lastname: Lam
authors.forename: Jagadish C
authors.initials: JC
authors.lastname: Ghosh
authors.forename: Nina M
authors.initials: NM
authors.lastname: Martin
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connell
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018925:Chemokines / Q000378:metabolism*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D041681:NIH 3T3 Cells; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018925:Chemokines; D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D021983:Cyclophilins