Mitochondrial Ca2+ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.

A three-step approach to minimise the impact of a mining site on vicuña (Vicugna vicugna) and to restore landscape connectivity.

Resource extraction projects generate a diversity of negative effects on the environment that are difficult to predict and mitigate. Consequently, adaptive management approaches have been advocated to develop effective responses to impacts that were not predicted. Mammal populations living in or around mine sites are frequently of management concern; yet, there is a dearth of published information on how to minimise the negative effects of different phases of mining operations on them. Here, we present the case study of a copper mine in the Chilean Altiplano, which caused roadkills of the protected vicuña (Vicugna vicugna). This issue led to a three-step solution being implemented: (1) the initial identification of the problem and implementation of an emergency response, (2) the scientific analysis for decision making and (3) the planning and informed implementation of responses for different future scenarios and timescales. The measures taken under each of these steps provide examples of environmental management approaches that make use of scientific information to develop integrated management responses. In brief, our case study showed how (1) the timescale and the necessity/urgency of the case were addressed, (2) the various stakeholders involved were taken into account and (3) changes were included into the physical, human and organisational elements of the company to achieve the stated objectives.

Astaxanthin Protects Primary Hippocampal Neurons against Noxious Effects of Aß-Oligomers.

Increased reactive oxygen species (ROS) generation and the ensuing oxidative stress contribute to Alzheimer's disease pathology. We reported previously that amyloid-ß peptide oligomers (AßOs) produce aberrant Ca(2+) signals at sublethal concentrations and decrease the expression of type-2 ryanodine receptors (RyR2), which are crucial for hippocampal synaptic plasticity and memory. Here, we investigated whether the antioxidant agent astaxanthin (ATX) protects neurons from AßOs-induced excessive mitochondrial ROS generation, NFATc4 activation, and RyR2 mRNA downregulation. To determine mitochondrial H2O2 production or NFATc4 nuclear translocation, neurons were transfected with plasmids coding for HyperMito or NFATc4-eGFP, respectively. Primary hippocampal cultures were incubated with 0.1 µM ATX for 1.5 h prior to AßOs addition (500 nM). We found that incubation with ATX (≤10 µM) for ≤24 h was nontoxic to neurons, evaluated by the live/dead assay. Preincubation with 0.1 µM ATX also prevented the neuronal mitochondrial H2O2 generation induced within minutes of AßOs addition. Longer exposures to AßOs (6 h) promoted NFATc4-eGFP nuclear translocation and decreased RyR2 mRNA levels, evaluated by detection of the eGFP-tagged fluorescent plasmid and qPCR, respectively. Preincubation with 0.1 µM ATX prevented both effects. These results indicate that ATX protects neurons from the noxious effects of AßOs on mitochondrial ROS production, NFATc4 activation, and RyR2 gene expression downregulation.

NF-kappaB activation by depolarization of skeletal muscle cells depends on ryanodine and IP3 receptor-mediated calcium signals.

Depolarization of skeletal muscle cells by either high external K(+) or repetitive extracellular field potential pulses induces calcium release from internal stores. The two components of this release are mediated by either ryanodine receptors or inositol 1,4,5-trisphosphate (IP(3)) receptors and show differences in kinetics, amplitude, and subcellular localization. We have reported that the transcriptional regulators including ERKs, cAMP/Ca(2+)-response element binding protein, c-fos, c-jun, and egr-1 are activated by K(+)-induced depolarization and that their activation requires IP(3)-dependent calcium release. We presently describe the activation of the nuclear transcription factor NF-kappaB in response to depolarization by either high K(+) (chronic) or electrical pulses (fluctuating). Calcium transients of relative short duration activate an NF-kappaB reporter gene to an intermediate level, whereas long-lasting calcium increases obtained by prolonged electrical stimulation protocols of various frequencies induce maximal activation of NF-kappaB. This activation is independent of extracellular calcium, whereas calcium release mediated by either ryanodine or IP(3) receptors contribute in all conditions tested. NF-kappaB activation is mediated by IkappaBalpha degradation and p65 translocation to the nucleus. Partial blockade by N-acetyl-l-cysteine, a general antioxidant, suggests the participation of reactive oxygen species. Calcium-dependent signaling pathways such as those linked to calcineurin and PKC also contribute to NF-kappaB activation by depolarization, as assessed by blockade through pharmacological agents. These results suggest that NF-kappaB activation in skeletal muscle cells is linked to membrane depolarization and depends on the duration of elevated intracellular calcium. It can be regulated by sequential activation of calcium release mediated by the ryanodine and by IP(3) receptors.