Tumor Suppressor p53 Restrains Cancer Cell Dissemination by Modulating Mitochondrial Dynamics

Abstract

Tumor suppressor p53 plays a central role in preventing tumorigenesis. Here, we unravel how p53 modulates mitochondrial dynamics to restrain the metastatic properties of cancer cells. p53 inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling to attenuate the protein level of mitochondrial fission process 1 (MTFP1), which fosters the pro-fission dynamin-related protein 1 (Drp1) phosphorylation. This regulatory mechanism allows p53 to restrict cell migration and invasion governed by Drp1-mediated mitochondrial fission. Downregulating p53 or elevating the molecular signature of mitochondrial fission correlates with aggressive tumor phenotypes and poor prognosis in cancer patients. Upon p53 loss, exaggerated mitochondrial fragmentation stimulates the activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling resulting in epithelial-to-mesenchymal transition (EMT)-like changes in cell morphology, accompanied by accelerated matrix metalloproteinase-9 (MMP9) expression and invasive cell migration. Notably, blocking the p53 deficiency-induced activation of mTORC1/MTFP1/Drp1/ERK axis completely abolishes the morphological switch, MMP9 expression, and cancer cell dissemination. Our findings unveil a hitherto unrecognized molecular mechanism underlying the metastatic phenotypes of p53-compromised cancers.

TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis

“…We have identified a novel role for TAp73 in regulating OPA1 expression and thereby mitochondrial morphology and function. This finding has numerous implications, as the control of mitochondrial dynamics by the p53 family is a key mechanism for the regulation of cell metabolism (including metabolic shifts observed in cancer) (49), tumour cell growth, dissemination (50), and differentiation (51). Indeed, previous evidence has shown that p53 regulates mitochondrial morphology through the transcriptional regulation of MFN2 (52).…”