Objectives We investigated the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy. Background Oxidative stress has been implicated in hypertensive cardiovascular diseases. Mitochondria and NADPH oxidase have been proposed as primary sites of reactive oxygen species (ROS) generation. Methods The mitochondrial targeted antioxidant peptide SS-31 was used to determine the role of mitochondrial oxidative stress in Angiotensin II (Ang)-induced cardiomyopathy, as well as in Gαq overexpressing mice with heart failure. Results Angiotensin II induces mitochondrial ROS in neonatal cardiomyocytes, which is prevented by SS-31, but not the non-targeted antioxidant N-acetyl cysteine (NAC). Continuous administration of Ang for 4 weeks in mice significantly increased both systolic and diastolic blood pressure, and this was not affected by SS-31 treatment. Ang was associated with upregulation of NADPH oxidase 4 (NOX4) expression, increased cardiac mitochondrial protein oxidative damage and induced the signaling for mitochondrial biogenesis. Reducing mitochondrial ROS by SS-31 substantially attenuated Ang-induced NOX4 upregulation, mitochondrial oxidative damage, upregulation of mitochondrial biogenesis, phosphorylation of p38 MAP kinase, and prevented apoptosis, concomitant with amelioration of Ang induced cardiac hypertrophy, diastolic dysfunction, and fibrosis, despite the absence of blood pressure lowering effect. NAC did not show any beneficial effect. SS-31 administration for 4 weeks also partially rescued the heart failure phenotype of Gαq overexpressing mice. Conclusions Mitochondrial targeted peptide SS-31 ameliorates cardiomyopathy resulting from prolonged Ang stimulation as well as Gαq overexpression, suggesting its potential clinical application for target organ protection in hypertensive cardiovascular diseases.

SUMMARY Significance of ERG in human prostate cancer is unclear because mouse prostate is resistant to ERG-mediated transformation. We determined that ERG activates the transcriptional program regulated by YAP1 of the Hippo signaling pathway and found that prostate-specific activation of either ERG or YAP1 in mice induces similar transcriptional changes and results in age-related prostate tumors. ERG binds to chromatin regions occupied by TEAD/YAP1 and transactivates Hippo target genes. In addition, in human luminal type prostate cancer cells, ERG binds to the promoter of YAP1 and is necessary for YAP1 expression. These results provide direct genetic evidence of a causal role for ERG in prostate cancer and reveal a connection between ERG and the Hippo signaling pathway.

Evolution of metazoans resulted in the specialization of cellular and tissue function. This was accomplished by division of labor, which allowed tissue parenchymal cells to prioritize their core functions while ancillary functions were delegated to tissue accessory cells, such as immune, stromal, and endothelial cells. In metabolic organs, the accessory cells communicate with their clients, the tissue parenchymal cells, to optimize cellular processes, allowing organisms to adapt to changes in their environment. Here, we discuss tissue immunometabolism from this vantage point, and use examples from adipose tissues (white, beige, and brown) and liver to outline the general principles by which accessory cells support metabolic homeostasis in parenchymal cells. A corollary of this model is that disruption of communication between client and accessory cells might predispose metabolic organs to the development of disease.

Adipose tissue provides a defense against starvation and environmental cold. These dichotomous functions are performed by three distinct cell types: energy-storing white adipocytes, and thermogenic beige and brown adipocytes. Previous studies have demonstrated that exposure to environmental cold stimulates the recruitment of beige adipocytes in the white adipose tissue (WAT) of mice and humans, a process that has been extensively investigated. However, beige adipose tissue also develops during the peri-weaning period in mice, a developmental program that remains poorly understood. Here, we address this gap in our knowledge using genetic, imaging, physiologic, and genomic approaches. We find that, unlike cold-induced recruitment in adult animals, peri-weaning development of beige adipocytes occurs in a temperature- and sympathetic nerve-independent manner. Instead, the transcription factor B cell leukemia/lymphoma 6 (BCL6) acts in a cell-autonomous manner to regulate the commitment but not the maintenance phase of beige adipogenesis. Genome-wide RNA-sequencing (seq) studies reveal that BCL6 regulates a core set of genes involved in fatty acid oxidation and mitochondrial uncoupling, which are necessary for development of functional beige adipocytes. Together, our findings demonstrate that distinct transcriptional and signaling mechanisms control peri-weaning development and cold-induced recruitment of beige adipocytes in mammals.

Brown adipocytes provide a metabolic defense against environmental cold but become dormant as mammals habituate to warm environments. Although dormancy is a regulated response in brown adipocytes to environmental warmth, its transcriptional mechanisms and functional importance are unknown. Here, we identify B cell leukemia/lymphoma 6 (BCL6) as a critical regulator of dormancy in brown adipocytes but not for their commitment, differentiation, or cold-induced activation. In a temperature-dependent manner, BCL6 suppresses apoptosis, fatty acid storage, and coupled respiration to maintain thermogenic fitness during dormancy. Mechanistically, BCL6 remodels the epigenome of brown adipocytes to enforce brown and oppose white adipocyte cellular identity. Thus, unlike other thermogenic regulators, BCL6 is specifically required for maintaining thermogenic fitness when mammals acclimate to environmental warmth.