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

Mitochondria control bioenergetics and cell fate decisions, but whether they also participate in extra-organelle signaling is not understood. Here, we show that interference with cyclophilin D (CypD), a mitochondrial matrix protein and apoptosis regulator, causes accelerated cell proliferation and enhanced cell migration and invasion. These responses are associated with global transcriptional changes in CypD-/- cells, predominantly affecting chemokines and their receptors, and resulting in increased activating phosphorylation of Signal Transduction and Activator of Transcription 3 (STAT3). In turn, STAT3 signaling promotes increased proliferation of CypD-/- cells via accelerated S-phase entry and supports Cxcl12-directed paracrine cell motility. Therefore, mitochondria-to-nuclei transcriptional signaling globally affects cell division and motility. As immunosuppressive therapies often target CypD, this pathway may predispose the tissue microenvironment of these patients to oncogenic transformation.

6

Tavecchio M, Lisanti S, Lam A, Ghosh JC, Martin NM, O'Connell M, Weeraratna AT, Kossenkov AV, Showe LC, Altieri DC