DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme A (CoA). Here, we show that all the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC) are also present and functional in the nucleus of mammalian cells. We found that knockdown of nuclear PDC in isolated functional nuclei decreased the de novo synthesis of acetyl-CoA and acetylation of core histones. Nuclear PDC levels increased in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress; this was accompanied by a corresponding decrease in mitochondrial PDC levels, suggesting a translocation from the mitochondria to the nucleus. Inhibition of nuclear PDC decreased acetylation of specific lysine residues on histones important for G1-S phase progression and expression of S phase markers. Dynamic translocation of mitochondrial PDC to the nucleus provides a pathway for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.

Alterations in the epigenome and metabolism both affect molecular rewiring in cancer cells and facilitate cancer development and progression. However, recent evidence suggests the existence of important bidirectional regulatory mechanisms between metabolic remodelling and the epigenome (specifically methylation and acetylation of histones) in cancer. Most chromatin-modifying enzymes require substrates or cofactors that are intermediates of cell metabolism. Such metabolites, and often the enzymes that produce them, can transfer into the nucleus, directly linking metabolism to nuclear transcription. We discuss how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis, as well as therapeutic responses.

The recent sequencing of the human genome has resulted in the addition of nine new hGLUT isoforms to the SLC2A family, many of which have widely varying substrate specificity, kinetic behavior, and tissue distribution. This review examines some new hypotheses related to the structure and function of these proteins.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of and that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

Most solid tumors are characterized by a metabolic shift from glucose oxidation to glycolysis, in part due to actively suppressed mitochondrial function, a state that favors resistance to apoptosis. Suppressed mitochondrial function may also contribute to the activation of hypoxia-inducible factor 1α (HIF1α) and angiogenesis. We have previously shown that the inhibitor of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA) activates glucose oxidation and induces apoptosis in cancer cells in vitro and in vivo. We hypothesized that DCA will also reverse the 'pseudohypoxic' mitochondrial signals that lead to HIF1α activation in cancer, even in the absence of hypoxia and inhibit cancer angiogenesis. We show that inhibition of PDKII inhibits HIF1α in cancer cells using several techniques, including HIF1α luciferase reporter assays. Using pharmacologic and molecular approaches that suppress the prolyl-hydroxylase (PHD)-mediated inhibition of HIF1α, we show that DCA inhibits HIF1α by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondria-derived α-ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H(2)O(2), as well as activation of GSK3β. Effective inhibition of HIF1α is shown by a decrease in the expression of several HIF1α regulated gene products as well as inhibition of angiogenesis in vitro in matrigel assays. More importantly, in rat xenotransplant models of non-small cell lung cancer and breast cancer, we show effective inhibition of angiogenesis and tumor perfusion in vivo, assessed by contrast-enhanced ultrasonography, nuclear imaging techniques and histology. This work suggests that mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity, in addition to the recently described pro-apoptotic and anti-proliferative effects, suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1α activation in solid tumors.

Although bulbar urethroplasty has a good stricture-free rate, patients with increased stricture length, increased overall comorbidity, obesity and strictures of infectious etiology are at higher risk for failure. These patients at risk should be counseled accordingly and perhaps be followed more closely after urethroplasty.

Introduction: We determine the preoperative identifiable risk factors during staging that predict stricture recurrence after urethroplasty. Methods: We conducted a retrospective review of all urethroplasties performed at a Canadian tertiary referral centre from 2003 to 2012. Failure was defined as a recurrent stricture <16 Fr on cystoscopic assessment. Multivariate analysis was calculated by Cox proportional hazard regression. Results: In total, 604 of 651 (93%) urethroplasties performed had adequate data with a mean follow-up of 52 months. Overall urethral patency was 90.7% with failures occurring between 2 weeks and 77 months postoperatively. The average time to recurrence was 11.7 months, with most patients with recurrence within 6 months (42/56; 75%). Multivariate regression identified Lichen sclerosus, iatrogenic, and infectious etiologies to be independently associated with stricture recurrence with hazard ratios (HR) (95% confidence interval) of 5.9 (2.1-16.5; p ≤ 0.001), 3.4 (1.2-10; p = 0.02), and 7.3 (2.3-23.7; p ≤ 0.001), respectively. Strictures ≥5cm recurred significantly more often (13.8% vs. 5.9%) with a HR 2.3 (1.2-4.5; p ≤ 0.01). Comorbidities, smoking, previous urethroplasty, stricture location and an age ≥50 were not associated with recurrence. Conclusion: Urethroplasty in general is an excellent treatment for urethral stricture with patency rates approaching 91%. While recurrences occur over 6 years after surgery, most (75%) recur within the first 6 months. Long segment strictures (≥5 cm), as well as Lichen sclerosus, infectious and iatrogenic etiologies, are associated with increased risk of recurrence. Limitations include the retrospective, single-centre nature of the study and the 7% loss to follow-up due to the centre being a regional referral one.

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