Myoglobin induces mitochondrial fusion to inhibit cancer cell proliferation and tumor growth

Emerging data demonstrates that the monomeric heme protein myoglobin is aberrantly expressed in breast cancer tumors and is associated with slower tumor growth and better patient prognosis. However, the mechanism by which myoglobin slows tumor growth is unknown. In this study we hypothesized that myoglobin regulates mitochondrial structure/function to inhibit cell proliferation. Using a model of MDA-MB-231 breast cancer cells, we showed that stably expressing human myoglobin decreased cell proliferation and induced cell cycle arrest (characterized by increase p21 and decreased cyclin E expression). We demonstrate that mechanistically this cell cycle arrest is due to the myoglobin-dependent oxidation and degradation of the ubiquitin ligase parkin, which results in an increase in the expression of mitofusin-1. This protein is known to induce mitochondrial fusion and inhibit cell cycle progression. These data are recapitulated in vivo in a murine xenograft model. These data suggest a novel role for myoglobin as a modulator of mitochondrial dynamics, cell proliferation, and tumor growth.