Abstract
Myoglobin is a monomeric heme protein expressed ubiquitously in skeletal and cardiac muscle and is traditionally considered to function as an oxygen reservoir for mitochondria during hypoxia. It is now well established that low concentrations of myoglobin are aberrantly expressed in a significant proportion of breast cancer tumors. Despite being expressed only at low levels in these tumors, myoglobin is associated with attenuated tumor growth and a better prognosis in breast cancer patients, but the mechanism of this myoglobin-mediated protection against further cancer growth remains unclear. Herein, we report a signaling pathway by which myoglobin regulates mitochondrial dynamics and thereby decreases cell proliferation. We demonstrate in vitro that expression of human myoglobin in MDA-MB-231, MDA-MB-468, and MCF7 breast cancer cells induces mitochondrial hyperfusion by up-regulating mitofusins 1 and 2, the predominant catalysts of mitochondrial fusion. This hyperfusion causes cell cycle arrest and subsequent inhibition of cell proliferation. Mechanistically, increased mitofusin expression was due to myoglobin-dependent free-radical production, leading to the oxidation and degradation of the E3 ubiquitin ligase parkin. We recapitulated this pathway in a murine model in which myoglobin-expressing xenografts exhibited decreased tumor volume with increased mitofusin, markers of cell cycle arrest, and decreased parkin expression. Furthermore, in human triple-negative breast tumor tissues, mitofusin and myoglobin levels were positively correlated. Collectively, these results elucidate a new function for myoglobin as a modulator of mitochondrial dynamics and reveal a novel pathway by which myoglobin decreases breast cancer cell proliferation and tumor growth by up-regulating mitofusin levels.
Highlights
Myoglobin is a monomeric heme protein expressed ubiquitously in skeletal and cardiac muscle and is traditionally considered to function as an oxygen reservoir for mitochondria during hypoxia
We demonstrate that myoglobin expression causes mitochondrial hyperfusion, leading to cell cycle arrest and inhibition of breast cancer cell proliferation
Myoglobin expression significantly decreases breast cancer cell proliferation in vitro In the first series of experiments, we sought to determine whether myoglobin expression altered proliferation of breast cancer cells
Summary
Myoglobin is a monomeric heme protein expressed ubiquitously in skeletal and cardiac muscle and is traditionally considered to function as an oxygen reservoir for mitochondria during hypoxia. We demonstrate in vitro that expression of human myoglobin in MDA-MB-231, MDAMB-468, and MCF7 breast cancer cells induces mitochondrial hyperfusion by up-regulating mitofusins 1 and 2, the predominant catalysts of mitochondrial fusion This hyperfusion causes cell cycle arrest and subsequent inhibition of cell proliferation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We demonstrate that this mitochondrial fusion is due to myoglobin-dependent oxidation and degradation of the E3 ubiquitin ligase parkin, leading to up-regulation of mitofusins 1 and 2, catalysts of mitochondrial fusion We show that this pathway is recapitulated in a murine model in which myoglobin expression attenuates tumor growth. The implications of this pathway for cancer cell biology and development of treatment are discussed along with the potential role of this signaling mechanism in human muscle physiology
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