Mitochondrial ryanodine receptors and other mitochondrial Ca2+ permeable channels

AbstractCa2+ channels that underlie mitochondrial Ca2+ transport first reported decades ago have now just recently been precisely characterized electrophysiologically. Numerous data indicate that mitochondrial Ca2+ uptake via these channels regulates multiple intracellular processes by shaping cytosolic and mitochondrial Ca2+ transients, as well as altering the cellular metabolic and redox state. On the other hand, mitochondrial Ca2+ overload also initiates a cascade of events that leads to cell death. Thus, characterization of mitochondrial Ca2+ channels is central to a comprehensive understanding of cell signaling. Here, we discuss recent progresses in the biophysical and electrophysiological characterization of several distinct mitochondrial Ca2+ channels

Type 1 ryanodine receptor in cardiac mitochondria: Transducer of excitation–metabolism coupling

AbstractMitochondria in a variety of cell types respond to physiological Ca2+ oscillations in the cytosol dynamically with Ca2+ uptakes. In heart cells, mitochondrial Ca2+ uptakes occur by a ruthenium red-sensitive Ca2+ uniporter (CaUP), a rapid mode of Ca2+ uptake (RaM) and a ryanodine receptor (RyR) localized in the inner mitochondrial membrane (IMM). Three subtypes of RyRs have been described and cloned, however, the subtype identity of the mitochondrial ryanodine receptor (mRyR) is unknown. Using subtype specific antibodies, we characterized the mRyR in the IMM from rat heart as RyR1. These results are substantiated by the absence of RyR protein in heart mitochondria from RyR1 knockout mice. The bell-shape Ca2+-dependent [3H]ryanodine binding curve and its modulation by caffeine and adenylylmethylenediphosphonate (AMPPCP) give further evidence that mRyR functions pharmacologically like RyR1. Ryanodine prevents mitochondrial Ca2+ uptake induced by raising extramitochondrial Ca2+ to 10 μM. Similarly, ryanodine inhibits oxidative phosphorylation stimulated by 10 μM extramitochondrial Ca2+. In summary, our results show that the mRyR in cardiac muscle has similar biochemical and pharmacological properties to the RyR1 in the sarcoplasmic reticulum (SR) of skeletal muscle. These results could also suggest an efficient mechanism by which mitochondria sequesters Ca2+ via mRyR during excitation–contraction coupling to stimulate oxidative phosphorylation for ATP production to meet metabolic demands. Thus, the mRyR functions as a transducer for excitation–metabolism coupling

Optimizing Radiology Peer Review: A Mathematical Model for Selecting Future Cases Based on Prior Errors

Introduction: Peer review is an essential process for physicians because it facilitates improved quality of patient care and continuing physician learning and improvement. However, peer review often is not well received by radiologists, who note that it is time intensive, subjective, and lacks demonstrable impact on patient care. Current advances in peer review include the RADPEER system with its standardization of discrepancies and incorporation of the peer review process into the PACS itself. Our purpose was to build on RADPEER and similar systems by using a mathematical model to optimally select the types of cases to be reviewed, for each radiologist undergoing review, based on the past frequency of interpretive error, likelihood of morbidity from an error, financial cost of an error, and time required for the reviewing radiologist to interpret the study. Methods: We compiled 612,890 preliminary radiology reports authored by residents and attendings of a large tertiary-care medical center from 1999 to 2004. Discrepancies between preliminary and final interpretations were classified by severity and validated by re-review of major discrepancies. A mathematical model was then used to calculate, for each author of a preliminary report, the combined morbidity and financial costs of expected errors across three modalities (MRI, CT, and CR) and four departmental divisions (Neuroradiology and Abdominal, Musculoskelatal, and Thoracic Imaging). Results: A customized report was generated for each on-call radiologist which determined the category (modality and body part) with the highest total cost function. A universal total cost based on probability data from all radiologists was also compiled. Conclusion: The use of mathematical models to guide case selection could optimize the efficiency and effectiveness of physician time spent on peer review and produce more concrete and meaningful feedback to radiologists undergoing peer review

Using the Integrated Behavioral Model to Predict High-Risk Drinking among College Students

This study assessed the Integrated Behavioral Model’s (IBM) utility in explaining high-risk drinking among college students. A total of 356 participants completed a four-page questionnaire based on the (IBM) theory and their drinking behavior. The results from a path analysis revealed three significant constructs (p\u3c0.05) which predicted intentions to engage in high-risk drinking: experiential attitude (0.34), injunctive norms (0.23), and self-efficacy (-0.28). The IBM explained approximately 45% and 26% of variance in intentions and high-risk drinking, respectively. Although limited in its use thus far, the IBM shows promise in its application

Application of singular perturbation methods for three-dimensional minimum-time interception

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76166/1/AIAA-20647-787.pd

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