Sex‐specific differences in mitochondrial function and free radical homeostasis are reported in the context of aging but not well‐established in pathogeneses occurring early in life. Here, we examine if sex disparity in mitochondria function, morphology, and redox status starts early and hence can be implicated in sexual dimorphism in cardiac as well as neurological disorders prevalent at young age. Although mitochondrial activity in the heart did not significantly vary between sexes, female brain exhibited enhanced respiration and higher reserve capacity. This was associated with lower H₂O₂production in female cardiac and brain tissues. Using transmission electron microscopy, we found that the number of female cardiac mitochondria is moderately greater (117 ± 3%,P = 0.049,N = 4) than male's, which increased significantly for cortical mitochondria (134 ± 4%,P = 0.001,N = 4). However, male's cardiac mitochondria exhibited fragmented, circular, and smaller mitochondria relative to female's mitochondria, while no morphologic sex‐dependent differences were observed in cortical mitochondria. No sex differences were detected in Nox2 and Nox4 proteins or O₂‐consuming/H₂O₂‐producing activities in brain homogenate or synaptosomes. However, a strong trend of increasedEPR‐detectedNOXsuperoxide in male synaptosomes hinted at higher superoxide dismutase activity in female brains, which was confirmed by two independent protocols. We also provide direct evidence that respiring mitochondria generally produce an order‐of‐magnitude lower reactive oxygen species (ROS) proportions than currently estimated. Our results indicate that sex differences in mitochondrial biogenesis, bioenergetics, and morphology may start at young age and that sex‐dependentSODcapacity may be responsible for differences inROShomeostasis in heart and brain.

Mevinolin (MVN) has been used clinically for the treatment of hypercholesterolemia with very good tolerance by patients. Based on epidemiological evidences, MVN was suggested strongly for the treatment of neoplasia. Early experimental trials suggested the mixed apoptotic/necrotic cell death pathway was activated in response to MVN exposure. Herein, the cytotoxic profile of MVN was evaluated, compared to the robust and frequently used anti-cancer drug doxorubicin (DOX), against breast (MCF-7), cervical (HeLa) and liver (HepG₂) transformed cell lines. MVN was showed comparable results in cytotoxic profile with DOX in all tested solid tumor cell lines. In addition, the MVN-induced cytotoxicity was inferred to be multi-factorial and not solely dependent on p53 expression. It was concluded that molecular and genetic assessment of MVN-induced cell death would be useful for developing cancer therapeutic treatments.

Triple-negative breast cancer (TNBC) subtype is among the most aggressive cancers with the worst prognosis and least therapeutic targetability while being more likely to spread and recur. Cancer transformations profoundly alter cellular metabolism by increasing glucose consumption via glycolysis to support tumorigenesis. Here we confirm that relative to ER-positive cells (MCF7), TNBC cells (MBA-MD-231) rely more on glycolysis thus providing a rationale to target these cells with glycolytic inhibitors. Indeed, iodoacetate (IA), an effective GAPDH inhibitor, caused about 70% drop in MDA-MB-231 cell viability at 20 μM while 40 μM IA was needed to decrease MCF7 cell viability only by 30% within 4 hours of treatment. However, the triple negative cells showed strong ability to recover after 24 h whereas MCF7 cells were completely eliminated at concentrations <10 μM. To understand the mechanism of MDA-MB-231 cell survival, we studied metabolic modulations associated with acute and extended treatment with IA. The resilient TNBC cell population showed a significantly greater count of cells with active mitochondria, lower apoptotic markers, normal cell cycle regulations, moderately lowered ROS, but increased mRNA levels of p27 and PARP1; all compatible with enhanced cell survival. Our results highlight an interplay between PARP and mitochondrial oxidative phosphorylation in TNBC that comes into play in response to glycolytic disruption. In the light of these findings, we suggest that combined treatment with PARP and mitochondrial inhibitors may provide novel therapeutic strategy against TNBC.