Myoglobin induces mitochondrial fusion, thereby inhibiting breast cancer cell proliferation.

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.

Nitrite Confers Preconditioning and Cytoprotection After Ischemia/Reperfusion Injury Through the Modulation of Mitochondrial Function.

SIGNIFICANCE: Nitrite is now recognized as an intrinsic signaling molecule that mediates a number of biological processes. One of the most reproducible effects of nitrite is its ability to mediate cytoprotection after ischemia/reperfusion (I/R). This robust phenomenon has been reproduced by a number of investigators in varying animal models focusing on different target organs. Furthermore, nitrite's cytoprotective versatility is highlighted by its ability to mediate delayed preconditioning and remote conditioning in addition to acute protection. RECENT ADVANCES: In the last 10 years, significant progress has been made in elucidating the mechanisms underlying nitrite-mediated ischemic tolerance. CRITICAL ISSUES: The mitochondrion, which is essential to both the progression of I/R injury and the protection afforded by preconditioning, has emerged as a major subcellular target for nitrite. This review will outline the role of the mitochondrion in I/R injury and preconditioning, review the accumulated preclinical studies demonstrating nitrite-mediated cytoprotection, and finally focus on the known interactions of nitrite with mitochondria and their role in the mechanism of nitrite-mediated ischemic tolerance. FUTURE DIRECTIONS: These studies set the stage for current clinical trials testing the efficacy of nitrite to prevent warm and cold I/R injury.

The impact of obesity and hypoxia on left ventricular function and glycolytic metabolism.

Abstract We have previously reported that 4 weeks of intermittent hypoxia (IH) exposure, mimicking the hypoxic stress of obstructive sleep apnea, produces compensatory increases in left ventricular (LV) contractility in lean C57BL/6J mice. In this study we compared the effects of 4 weeks IH to 4 weeks of sustained hypoxia (SH) on LV function and cardiac glycolysis in lean C57BL/6J mice and obese ob/ob mice at 10-12 weeks of age. The four exposure conditions were IH (nadir O2 [5-6%] at 60 cycles/h during the 12 h light period), SH (24 h inspired O2 [10%]), and control groups of intermittent air (IA) or room air. Cardiac function was assessed under isoflurane anesthesia (1-2%) by echocardiography and pressure-volume loop analysis and myocardial glycolytic rates were determined ex vivo using radiolabeled (3)H-glucose. Lean mice exposed to IH exhibited increases in contractile parameters which were associated with elevated glycolytic rates (3.4 vs. 5.7 µg/µL·g; P < 0.05). Ob/ob mice did not show any improvements in contractility after IH. Moreover, cardiac glycolytic rates and LV systolic and diastolic function did not differ from IA ob/ob controls. Following SH exposure, lean mice exhibited increased contractility and glycolytic rates (3.8 vs. 5.7 µg/µL·g; P < 0.05), however, LV lumen dimensions were reduced. In contrast, ob/ob mice exposed to SH show compromised systolic and diastolic function associated with unchanging glycolytic rates. These findings demonstrate that, in a murine model of obesity, an inability to increase glycolysis is associated with an absence of an adaptive cardiac response to IH and marked systolic and diastolic dysfunction in response to SH.