Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumorprogression and cell invasion

Recently we showed that partial depletion of mitochondrial DNA (genetic str ess) or treatment with mitochondrial-specific inhibitors (metabolic stress) induced a stress signaling that was associated with increased cytoplasmic- free Ca2+ [Ca2+](c). In the present study we show that the mitochondria-to- nucleus stress signaling induces invasive phenotypes in otherwise non-invas ive C2C12 myoblasts and human pulmonary carcinoma A549 cells. Tumor-specifi c markers cathepsin L and transforming growth factor beta (TGF beta) are ov erexpressed in cells subjected to mitochondrial genetic as well as metaboli c stress, C2C12 myoblasts subjected to stress showed 4- to 6-fold higher in vasion through reconstituted Matrigel membrane as well as rat tracheal xeno transplants in Scid mice. Activation of Ca2+-dependent protein kinase C (PK C) under both genetic and metabolic stress conditions was associated with i ncreased cathepsin L gene expression, which contributes to increased invasi ve property of cells. Reverted cells with similar to 70% of control cell mt DNA exhibited marker mRNA contents, cell morphology and invasive property c loser to control cells. These results provide insights into a new pathway b y which mitochondrial DNA and membrane damage can contribute to tumor progr ession and metastasis.