Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals

The recent identification of the mitochondrial Ca(2+) uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca(2+) uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca(2+) levels following NMDA receptor activation, leading to increased mitochondrial membrane depolarization and excitotoxic cell death. Knockdown of endogenous Mcu expression reduces NMDA-induced increases in mitochondrial Ca(2+), resulting in lower levels of mitochondrial depolarization and resistance to excitotoxicity. Mcu is subject to dynamic regulation as part of an activity-dependent adaptive mechanism that limits mitochondrial Ca(2+) overload when cytoplasmic Ca(2+) levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca(2+) and CaM kinase-mediated induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca(2+) uptake and preventing excitotoxic death. This establishes Mcu and the pathways regulating its expression as important determinants of excitotoxicity, which may represent therapeutic targets for excitotoxic disorders

Mitochondrial Ca2+ Overload Underlies Aβ Oligomers Neurotoxicity Providing an Unexpected Mechanism of Neuroprotection by NSAIDs

Dysregulation of intracellular Ca2+ homeostasis may underlie amyloid β peptide (Aβ) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Aβ1–42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Aβ fibrils, induce a massive entry of Ca2+ in neurons and promote mitochondrial Ca2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Aβ oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca2+ overload, cytochrome c release and cell death induced by Aβ oligomers. Our results indicate that i) mitochondrial Ca2+ overload underlies the neurotoxicity induced by Aβ oligomers and ii) inhibition of mitochondrial Ca2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Aβ oligomers and AD

Stimulation‐Induced Mitochondrial [Ca 2+

Changes in mitochondrial matrix [Ca(2+)] evoked by trains of action potentials were studied in levator auris longus motor terminals using Ca(2+)-sensitive fluorescent indicator dyes (rhod-2, rhod-5F). During a 2500 impulse 50 Hz train, mitochondrial [Ca(2+)] in most wild-type terminals increased within 5–10 s to a plateau level that was sustained until stimulation ended. This plateau was not due to dye saturation, but rather reflects a powerful buffering system within the mitochondrial matrix. The amplitude of this plateau was similar for stimulation frequencies in the range 15–100 Hz. Plateau amplitude was sensitive to temperature, with no detectable stimulation-induced increase in fluorescence at temperatures below 17 °C, and increasing magnitudes as temperature was increased to near-physiological levels (38 °C). When stimulation ended, mitochondrial [Ca(2+)] decayed slowly back to prestimulation levels over a time course of hundreds of seconds. Similar measurements were also made in motor terminals of mice expressing the G93A mutation of human superoxide dismutase 1 (SOD1-G93A). In mice > 100 days old, all of whom exhibited hindlimb paralysis, some terminals continued to show wild-type mitochondrial [Ca(2+)] responses, but in other terminals mitochondrial [Ca(2+)] did not plateau, but rather continued to increase throughout most of the stimulus train. Thus mechanism(s) that limit stimulation-induced increases in mitochondrial [Ca(2+)] may be compromised in some SOD1-G93A terminals

The role of the boundaries in the organisation of geographical space in Latvia

ANOTĀCIJA Mūsdienu globalizācijas procesos valstu politisko robežu nozīmes samazināšanās apstākļos pieaug interese par robežu pētījumiem dažādos mērogos – robežas kļūst būtiskas reģionālā un lokālā līmenī. Latvijā pēdējā desmitgadē ir notikuši aktīvi teritoriālās politikas procesi veidojot jaunu administratīvu, pārvaldes struktūru, telpiski bāzētus attīstības instrumentus, kur nozīmīgu vietu ieņem robežas. Līdzšinējie Pētījumi, kas saistīti ar teritorijām Latvijā, neskata robežu kā pētījumu objektu. Robeža kā domāšanas un telpiskās rīcības produkts izpaužas teritoriālajās politikās kā līdzeklis un atspoguļojums. Pētījuma pieeja pamatojas uz ģeogrāfiskās ontoloģijas pētījumiem, kas Latvijā nav pazīstami un izmantoti. Darba lietotā pieeja skata robežas kā attiecību telpu, kas veidojas plānošanas procesā caur privātā – publiskā attiecību prizmu Pierīgas un Piekrastes robežtelpās. Robežas izpaužas kā juridisks, fizisks un sociālo attiecību fenomens, kas ir robežtelpu analīzes fokusi. Darbs balstās uz plānošanas dokumentu, kartogrāfiskās informācijas analīzi, intervijām, teritorijas apsekojumiem, foto fiksāciju un rezultātu interpretāciju. Darbā analizēta robežu kā fenomena, domāšanas produkta un rīcību instrumenta loma tās ietekmēs. Ir izstrādāta un aprobēta pieeja robežu pētīšanai, kas balstās uz robežtelpu konceptu teritoriālās praksēs Latvijā. Darbā izvērtēta robežu loma un izmantošanas iespējas teritorijas apsaimniekošanā un plānošanā. Darbu veido piecas daļas. Pirmajā daļā analizēti robežu pētījumi no ontoloģijas, funkcionālā un lietišķā aspekta un pamatota darbā lietoto pieeja. Otrā daļa pamato darbā lietotās metodes. Trešā daļa analizē formālās, funkcionālās un attiecību robežas un to darbību Pierīgas un Piekrastes robežtelpās dažādu privātā – publiskā attiecību gadījumos. Ceturtā daļa apkopo ieteikumus, priekšlikumus un diskusiju jautājumus. Piektā sadaļa apkopo atziņas un secinājumus.ANNOTATION In current globalisation and in the situation of the diminishing role of state boundaries at the same time there is an increasing interest about boundary studies on different scales, particularly at the regional and local level. The last decade has been characterized by active territorial policies in Latvia, creating a new administrative and governance structure and spatial development instruments where boundaries play an important role. Researches in connection with territories do not consider boundaries as an object of research in Latvia. A Boundary as a cognitive and spatial performing product represents in territorial policies as a tool and a reflection. The research approach has been based on ontological studies, which are new and not used in Latvia. With the help of the research approach used in the doctoral thesis boundaries have been looked as relation space which is formed in planning processes through the prism of public-private relations in Riga suburban and Coastal border spaces. A Boundary as a juridical, physical and social relational phenomenon is a focal point of study. The thesis has been based on the analysis and interpretation of planning documents, cartographic information, interviews, field research and photo fixation. The doctoral thesis analyse the role of boundaries as a phenomenon, a cognitive product and an instrument of spatial action in their impacts. The research approach based on the Border space concept has been elaborated and approbated in territorial practices in Latvia. The thesis analyse the role and the possibilities of application of boundaries in land management and planning. The doctoral thesis consists of five parts. Part 1 includes boundaries studies from ontological, functional and applied aspects and substitute approach used in the work. Part 2 explains the methods used in the work. Part 3 analyses formal, functional and relational boundaries and their role in Suburban and Coastal border spaces in different cases of public - private relations. Part 4 summarizes suggestions, recommendations and discussions. Part 5 includes conclusions