Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling.

SIGNIFICANCE: Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics of mitochondrial ion transport mechanisms have been extensively studied for several decades, the majority of the molecular identities that are responsible for these channels/transporters have remained a mystery until very recently. RECENT ADVANCES: Recent breakthrough studies uncovered the molecular identities of the diverse array of major mitochondrial ion channels/transporters, including the mitochondrial Ca2+ uniporter pore, mitochondrial permeability transition pore, and mitochondrial ATP-sensitive K+ channel. This new information enables us to form detailed molecular and functional characterizations of mitochondrial ion channels/transporters and their roles in mitochondrial redox signaling. CRITICAL ISSUES: Redox-mediated post-translational modifications of mitochondrial ion channels/transporters and ETC serve as key mechanisms for the spatiotemporal control of mitochondrial ROS/RNS generation. FUTURE DIRECTIONS: Identification of detailed molecular mechanisms for redox-mediated regulation of mitochondrial ion channels will enable us to find novel therapeutic targets for many diseases that are associated with cellular redox signaling and mitochondrial ion channels/transporters

Molecular and functional identification of a mitochondrial ryanodine receptor in neurons.

Mitochondrial Ca(2+) controls numerous cell functions, such as energy metabolism, reactive oxygen species generation, spatiotemporal dynamics of Ca(2+) signaling, cell growth and death in various cell types including neurons. Mitochondrial Ca(2+) accumulation is mainly mediated by the mitochondrial Ca(2+) uniporter (MCU), but recent reports also indicate that mitochondrial Ca(2+)-influx mechanisms are regulated not only by MCU, but also by multiple channels/transporters. We previously reported that ryanodine receptor (RyR), which is a one of the main Ca(2+)-release channels at endoplasmic/sarcoplasmic reticulum (SR/ER) in excitable cells, is expressed at the mitochondrial inner membrane (IMM) and serves as a part of the Ca(2+) uptake mechanism in cardiomyocytes. Although RyR is also expressed in neuronal cells and works as a Ca(2+)-release channel at ER, it has not been well investigated whether neuronal mitochondria possess RyR and, if so, whether this mitochondrial RyR has physiological functions in neuronal cells. Here we show that neuronal mitochondria express RyR at IMM and accumulate Ca(2+) through this channel in response to cytosolic Ca(2+) elevation, which is similar to what we observed in another excitable cell-type, cardiomyocytes. In addition, the RyR blockers dantrolene or ryanodine significantly inhibits mitochondrial Ca(2+) uptake in permeabilized striatal neurons. Taken together, we identify RyR as an additional mitochondrial Ca(2+) uptake mechanism in response to the elevation of [Ca(2+)]c in neurons, suggesting that this channel may play a critical role in mitochondrial Ca(2+)-mediated functions such as energy metabolism

Isoform-specific dynamic translocation of PKC by α1-adrenoceptor stimulation in live cells.

Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated downstream of Gq-protein coupled receptor (GqPCR) signaling and translocate to various cellular compartments including plasma membrane (PM). Recent reports suggested that different types of GqPCRs would activate different PKC isoforms (classic, novel and atypical PKCs) with different trafficking patterns. However, the knowledge of isoform-specific activation of PKC by each GqPCR is limited. α1-Adrenoceptor (α1-AR) is one of the GqPCRs highly expressed in the cardiovascular system. In this study, we examined the isoform-specific dynamic translocation of PKC in living HEK293T cells by α1-AR stimulation (α1-ARS). Rat PKCα, βI, βII, δ, ε and ζ fused with GFP at C-term were co-transfected with human α1A-AR into HEK293T cells. The isoform-specific dynamic translocation of PKC in living HEK293T cells by α1-ARS using phenylephrine was measured by confocal microscopy. Before stimulation, GFP-PKCs were localized at cytosolic region. α1-ARS strongly and rapidly translocated a classical PKC (cPKC), PKCα, (\u3c30 \u3es) to PM, with PKCα returning diffusively into the cytosol within 5 min. α1-ARS rapidly translocated other cPKCs, PKCβI and PKCβII, to the PM (\u3c30 \u3es), with sustained membrane localization. One novel PKC (nPKC), PKCε, but not another nPKC, PKCδ, was translocated by α1-AR stimulation to the PM (\u3c30 \u3es) and its membrane localization was also sustained. Finally, α1-AR stimulation did not cause a diacylglycerol-insensitive atypical PKC, PKCζ translocation. Our data suggest that PKCα, β and ε activation may underlie physiological and pathophysiological responses of α1-AR signaling for the phosphorylation of membrane-associated substrates including ion-channel and transporter proteins in the cardiovascular system

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

PERAN SERTA ORANG TUA DALAM PENDIDIKAN KARAKTER ANAK

Abstrak. Pendidikan karakter merupakan kebutuhan yang digunakan secara berkelanjutan guna untuk membangkitkan serta menguatkan suatu kesadaran seseorang bahwa masa yang akan datang masa dimana yang lebih baik lagi haruslah diupayakan dengan membangun serta menguatkan karakter seseorang karena pendidikan karakter tidak hanya dibutuhkan di sekolah saja namun di lingkungan sosial juga . Belakangan ini banyak sekali kenakalan anak diusia yang masih sangat belia yang menandakan kurangnya pendidikan karakter di sekitarnya. Dalam menumbuhkan pendidikan karakter seseorang perlu adanya kesadaran dari berbagai pihak untuk pembentukan suatu karakter seseorang. Salah satu pihak yang paling utama untuk membentuk karakter seseorang ialah orang tua. Orang tua adalah pondasi dalam segala pembentukan karakter seorang anak. Peran orang tua sangat mempengaruhi pembentukan karakter anak. Termasuk itu motivasi, dukungan serta ada dan tidaknya orang tua di kehidupan sehari-hari anak. Pendidikan karakter juga perlu diajarkan baik di sekolah maupun di rumah dan bahkan di lingkungn sekitar untuk membentuk anak yang memiliki akhlak dan kepribadian yang baik. Kata  Kunci: Pendidikan Karakter, Peran Orang Tua Abstract. Character education is a need that is used on an ongoing basis in order to arouse and strengthen a person's awareness that a future where a better time must be pursued by building and strengthening one's character because character education is not only needed in schools, but also in the social environment. Lately, there are a lot of delinquents in young children who are still very young, which indicates a lack of character education around them. In growing one's character education there needs to be awareness of various parties for the formation of a person's character. One of the most important parties to shape a person's character is parents. Parents are the foundation in all the formation of a child's character. The role of parents greatly influences the formation of the child's character. Including motivation, support and the presence or absence of parents in the daily life of children. Character education also needs to be taught both at school and at home and even in the environment to form children who have good character and personality. Keywords: Character Education, Parents' Roles