Pilar Alvarez

Universidad de Valladolid | UVA · IBGM/Medicine

Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium unip...

Introduction: The high prevalence of neurodegenerative diseases in our population and the lack of effective treatments encourage the search for new therapeutic targets for these pathologies. We have recently described that submaximal inhibition of the Sarco-Endoplasmic Reticulum Ca ²⁺ ATPase (SERCA), the main responsible for ER calcium storage, is...

Glucose sensing in pancreatic beta-cells depends on oxidative phosphorylation and mitochondria-derived signals that promote insulin secretion. Using mass spectrometry-based phosphoproteomics to search for down-stream effectors of glucose dependent signal transduction in INS-1E insulinoma cells, we identified the outer mitochondrial membrane protein...

The molecular mechanisms that mediate and regulate calcium (Ca2+) fluxes through the membranes of intracellular organelles play a key role in the generation and shaping of the local and global cytosolic Ca2+ signals triggering the process of regulated exocytosis in chromaffin cells. Beyond that role, intraorganellar Ca2+ homeostasis also regulates...

Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in i...

Neural circuits coordinate with muscles and sensory feedback to generate motor behaviors appropriate to an animal’s environment. In C. elegans, the mechanisms by which the motor circuit generates undulations and modulates them based on the environment are largely unclear. We quantitatively analyzed C. elegans locomotion during free movement and dur...

We have reported recently that the mitochondrial Na⁺/Ca²⁺ exchanger inhibitor CGP37157 extends lifespan in Caenorhabditis elegans by a mechanism involving mitochondria, the TOR pathway and the insulin/IGF1 pathway. Here we show that CGP37157 significantly improved the evolution with age of the sarcomeric regular structure, delaying development of s...

We have reported recently that submaximal inhibition of the Sarco Endoplasmic Reticulum Ca²⁺ ATPase (SERCA) produces an increase in the lifespan of C. elegans worms. We have explored here the mechanism of this increased survival by studying the effect of SERCA inhibition in several mutants of signaling pathways related to longevity. Our data show t...

Mitochondrial [Ca2+] plays an important role in the regulation of mitochondrial function, controlling ATP production and apoptosis triggered by mitochondrial Ca2+ overload. This regulation depends on Ca2+ entry into the mitochondria during cell activation processes, which is thought to occur through the mitochondrial Ca2+ uniporter (MCU). Here, we...

Ca2+ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca2+ signaling is one of the key events in the development of neurodegenerative processes, an idea called the “calc...

The benzothiazepine CGP37157 has shown neuroprotective effects in several in vitro models of excitotoxicity involving dysregulation of intracellular Ca2+ homeostasis. Although its mechanism of neuroprotection is unclear, it is probably related with some of its effects on Ca2+ homeostasis. CGP37157 is a well-known inhibitor of the mitochondrial Na+/...

The 5' AMP-activated protein kinase (AMPK) is a nutrient-sensitive kinase that plays a key role in the control of cellular energy metabolism. We have explored here the relationship between AMPK and Ca²⁺ signaling by looking at the effect of an AMPK activator (A769662) and an AMPK inhibitor (dorsomorphin) on histamine-induced Ca²⁺-release from the e...

The sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) refills the endoplasmic reticulum (ER) with Ca²⁺ up to the millimolar range and is therefore the main controller of the ER [Ca²⁺] level ([Ca²⁺]ER), which has a key role in the modulation of cytosolic Ca²⁺ signaling and ER-mitochondria Ca²⁺ transfer. Given that both cytosolic and mitochondrial Ca²⁺...

Coordinated rhythmic movements are ubiquitous in animal behavior. In many organisms, chains of neural oscillators underlie the generation of these rhythms. In C. elegans, locomotor wave generation has been poorly understood; in particular, it is unclear where in the circuit rhythms are generated, and whether there exists more than one such generato...

Coordinated rhythmic movements are ubiquitous in animal behavior. In many organisms, chains of neural oscillators underlie the generation of these rhythms. In C. elegans , locomotor wave generation has been poorly understood; in particular, it is unclear where in the circuit rhythms are generated, and whether there exists more than one such generat...

Progressive decline in mitochondrial function is generally considered one of the hallmarks of aging. We have expressed a Ca2+ sensor in the mitochondrial matrix of C. elegans pharynx cells and we have measured for the first time mitochondrial [Ca2+] ([Ca2+]M) dynamics in the pharynx of live C. elegans worms during aging. Our results show that worms...

Ca?? is a key signal transducer for muscle contraction. Continuous in vivo monitoring of intracellular Ca??-dynamics in C. elegans pharynx muscle revealed surprisingly complex Ca?? patterns. Despite the age-dependent decline of pharynx pumping, we observed unaltered fast Ca?? oscillations both in young and old worms. In addition, sporadic prolonged...

The role of mitochondria in intracellular Ca2+ signaling relies mainly in its capacity to take up Ca2+ from the cytosol and thus modulate the cytosolic [Ca2+]. Because of the low Ca2+-affinity of the mitochondrial Ca2+-uptake system, this organelle appears specially adapted to take up Ca2+ from local high-Ca2+ microdomains and not from the bulk cyt...

MICU1 and MICU2 are the main regulators of the mitochondrial Ca(2+)-uniporter (MCU), but their precise functional role is still under debate. We show here that MICU2 behaves as a pure inhibitor of MCU at low cytosolic [Ca(2+)] ([Ca(2+)]c), though its effects decrease as [Ca(2+)]c is increased an disappear above 7 μM. Regarding MICU1, studying its e...