Targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity.

A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis.

ICOS controls Foxp3(+) regulatory T-cell expansion, maintenance and IL-10 production during helminth infection.

Foxp3(+) regulatory T (Treg) cells are key immune regulators during helminth infections, and identifying the mechanisms governing their induction is of principal importance for the design of treatments for helminth infections, allergies and autoimmunity. Little is yet known regarding the co-stimulatory environment that favours the development of Foxp3(+) Treg-cell responses during helminth infections. As recent evidence implicates the co-stimulatory receptor ICOS in defining Foxp3(+) Treg-cell functions, we investigated the role of ICOS in helminth-induced Foxp3(+) Treg-cell responses.

Mitochondria determine the differentiation potential of cardiac mesoangioblasts.

An understanding of cardiac progenitor cell biology would facilitate their therapeutic potential for cardiomyocyte restoration and functional heart repair. Our previous studies identified cardiac mesoangioblasts as precommitted progenitor cells from the postnatal heart, which can be expanded in vitro and efficiently differentiated in vitro and in vivo to contribute new myocardium after injury.Based on their proliferation potential in culture, we show here that two populations of mesoangioblasts can be isolated from explant cultures of mouse and human heart.

Mitochondrial reactive oxygen species mediate cardiomyocyte formation from embryonic stem cells in high glucose.

Accumulating evidence points to reactive oxygen species (ROS) as important signaling molecules for cardiomyocyte differentiation in embryonic stem (ES) cells. Given that ES cells are normally maintained and differentiated in medium containing supraphysiological levels of glucose (25 mM), a condition which is known to result in enhanced cellular ROS formation, we questioned whether this high glucose concentration was necessary for cardiomyocyte lineage potential. We show here that ES cells cultured in physiological glucose (5 mM), maintained their general stemness qualities but displayed an altered mitochondrial metabolism, which resulted in decreased ROS production.

Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells.

Remodelling of mitochondrial metabolism is a hallmark of cancer. Mutations in the genes encoding succinate dehydrogenase (SDH), a key Krebs cycle component, are associated with hereditary predisposition to pheochromocytoma and paraganglioma, through mechanisms which are largely unknown. Recently, the jumonji-domain histone demethylases have emerged as a novel family of 2-oxoglutarate-dependent chromatin modifiers with credible functions in tumourigenesis.

Cells silenced for SDHB expression display characteristic features of the tumor phenotype.

Recently, enzymes of the tricarboxylic acid (TCA) cycle have emerged as novel tumor suppressors. In particular, mutations in the nuclear-encoded subunits of succinate dehydrogenase (SDHB, SDHC, and SDHD) cause paragangliomas and pheochromocytomas. Although the mechanism(s) by which disruption of mitochondrial metabolism leads to neoplasia is largely unknown, increasing evidence points to an activation of pseudohypoxia.

An alternatively spliced transcript of the PHD3 gene retains prolyl hydroxylase activity.

Cellular response to limiting oxygen levels is managed, in part, by the transcription factor hypoxia-inducible factor 1 (HIF-1), and the prolyl hydroxylase (PHD) family of oxygen-requiring enzymes. In the process of analyzing the expression of PHD3, we observed the presence of two alternatively processed PHD3 transcripts, designated PHD3Delta1 and PHD3Delta4 . The expression of both PHD3 and PHD3Delta1 was observed in all tissues and cell lines tested, although the expression of the novel PHD3Delta4 appeared to be restricted to primary cancer tissues.

A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1alpha.

Exposure to limiting oxygen in cells and tissues induce the stabilization and transcriptional activation of the hypoxia-inducible factor 1 alpha (HIF-1alpha) protein, a key regulator of the hypoxic response. Reactive oxygen species (ROS) generation has been implicated in the stabilization of HIF-1alpha during this response, but this is still a matter of some debate. In this study we utilize a mitochondria-targeted antioxidant, mitoubiquinone (MitoQ), and examine its effects on the hypoxic stabilization of HIF-1alpha.