Superoxide flashes in single mitochondria

In quiescent cells, mitochondria are the primary source of reactive oxygen species (ROS), which are generated by leakiness of the electron transport chain (ETC). High levels of ROS can trigger cell death, whereas lower levels drive diverse and important cellular functions. We show here by employing a newly developed mitochondrial matrix-targeted superoxide indicator, that individual mitochondria undergo spontaneous bursts of superoxide generation, termed "superoxide flashes." Superoxide flashes occur randomly in space and time, exhibit all-or-none properties, and provide a vital source of superoxide production across many different cell types. Individual flashes are triggered by transient openings of the mitochondrial permeability transition pore stimulating superoxide production by the ETC. Furthermore, we observe a flurry of superoxide flash activity during reoxygenation of cardiomyocytes after hypoxia, which is inhibited by the cardioprotective compound adenosine. We propose that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases.     

表观遗传调控植物响应非生物胁迫的研究进展

植物的生长发育容易受到外界环境变化的影响。非生物胁迫发生时, 表观遗传机制对胁迫应答基因的表达调控发挥了十分重要的作用。近年来, 调控植物非生物胁迫应答的表观遗传机制研究取得了一系列重要进展, 为进一步深入解析植物响应非生物胁迫的分子机制奠定了基础。该文对DNA甲基化修饰、组蛋白修饰、染色质重塑和非编码RNA等主要表观遗传调控方式在植物响应非生物胁迫中的作用进行了简要综述。     

LncRNA OIP5-AS1-directed miR-7 degradation promotes MYMX production during human myogenesis

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) modulate gene expression programs in physiology and disease. Here, we report a noncoding RNA regulatory network that modulates myoblast fusion into multinucleated myotubes, a process that occurs during muscle development and muscle regeneration after injury. In early stages of human myogenesis, the levels of lncRNA OIP5-AS1 increased, while the levels of miR-7 decreased. Moreover, OIP5-AS1 bound and induced miR-7 decay via target RNA-directed miRNA decay; accordingly, loss of OIP5-AS1 attenuated, while antagonizing miR-7 accelerated, myotube formation. We found that the OIP5-AS1-mediated miR-7 degradation promoted myoblast fusion, as it derepressed the miR-7 target MYMX mRNA, which encodes the fusogenic protein myomixer (MYMX). Remarkably, an oligonucleotide site blocker interfered with the OIP5-AS1-directed miR-7 degradation, allowing miR-7 to accumulate, lowering MYMX production and suppressing myotube formation. These results highlight a mechanism whereby lncRNA OIP5-AS1-mediated miR-7 decay promotes myotube formation by stimulating a myogenic fusion program.     

Artificial neural network method for predicting HIV protease cleavage sites in protein

Knowledge of the polyprotein cleavage sites by HIV protease will refine our understanding of its specificity, and the information thus acquired will be useful for designing specific and efficient HIV protease inhibitors. The search for inhibitors of HIV protease will be greatly expedited if one can find and accurate, robust, and rapid method for predicting the cleavage sites in proteins by HIV protease. In this paper, Kohonen’s self-organization model, which uses typical artificial neural networks, is applied to predict the cleavability of oligopeptides by proteases with multiple and extended specificity subsites. We selected HIV-1 protease as the subject of study. We chose 299 oligopeptides for the training set, and another 63 oligopeptides for the test set. Because of its high rate of correct prediction (58/63=92.06%) and stronger fault-tolerant ability, the neural network method should be a useful technique for finding effective inhibitors of HIV protease, which is one of the targets in designing potential drugs against AIDS. The principle of the artificial neural network method can also be applied to analyzing the specificity of any multisubsite enzyme.     

Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress

In response to endoplasmic reticulum (ER) stress, cells launch homeostatic and protective responses, but can also activate cell death cascades. A 54 kDa integral ER membrane protein called Herp was identified as a stress-responsive protein in non-neuronal cells. We report that Herp is present in neurons in the developing and adult brain, and that it is regulated in neurons by ER stress; sublethal levels of ER stress increase Herp levels, whereas higher doses decrease Herp levels and induce apoptosis. The decrease in Herp protein levels following a lethal ER stress occurs prior to mitochondrial dysfunction and cell death, and is mediated by caspases which generate a 30-kDa proteolytic Herp fragment. Mutagenesis of the caspase cleavage site in Herp enhances its neuroprotective function during ER stress. While suppression of Herp induction by RNA interference sensitizes neural cells to apoptosis induced by ER stress, overexpression of Herp promotes survival by a mechanism involving stabilization of ER Ca(2+) levels, preservation of mitochondrial function and suppression of caspase 3 activation. ER stress-induced activation of JNK/c-Jun and caspase 12 are reduced by Herp, whereas induction of major ER chaperones is unaffected. Herp prevents ER Ca(2+) overload under conditions of ER stress and agonist-induced ER Ca(2+) release is attenuated by Herp suggesting a role for Herp in regulating neuronal Ca(2+) signaling. By stabilizing ER Ca(2+) homeostasis and mitochondrial functions, Herp serves a neuroprotective function under conditions of ER stress.     

Artificial neural network method for predicting HIV protease cleavage sites in protein

Knowledge of the polyprotein cleavage sites by HIV protease will refine our understanding of its specificity, and the information thus acquired will be useful for designing specific and efficient HIV protease inhibitors. The search for inhibitors of HIV protease will be greatly expedited if one can find and accurate, robust, and rapid method for predicting the cleavage sites in proteins by HIV protease. In this paper, Kohonen’s self-organization model, which uses typical artificial neural networks, is applied to predict the cleavability of oligopeptides by proteases with multiple and extended specificity subsites. We selected HIV-1 protease as the subject of study. We chose 299 oligopeptides for the training set, and another 63 oligopeptides for the test set. Because of its high rate of correct prediction (58/63=92.06%) and stronger fault-tolerant ability, the neural network method should be a useful technique for finding effective inhibitors of HIV protease, which is one of the targets in designing potential drugs against AIDS. The principle of the artificial neural network method can also be applied to analyzing the specificity of any multisubsite enzyme.     

Mitochondria and neuroplasticity

The production of neurons from neural progenitor cells, the growth of axons and dendrites and the formation and reorganization of synapses are examples of neuroplasticity. These processes are regulated by cell-autonomous and intercellular (paracrine and endocrine) programs that mediate responses of neural cells to environmental input. Mitochondria are highly mobile and move within and between subcellular compartments involved in neuroplasticity (synaptic terminals, dendrites, cell body and the axon). By generating energy (ATP and NAD⁺), and regulating subcellular Ca²⁺ and redox homoeostasis, mitochondria may play important roles in controlling fundamental processes in neuroplasticity, including neural differentiation, neurite outgrowth, neurotransmitter release and dendritic remodelling. Particularly intriguing is emerging data suggesting that mitochondria emit molecular signals (e.g. reactive oxygen species, proteins and lipid mediators) that can act locally or travel to distant targets including the nucleus. Disturbances in mitochondrial functions and signalling may play roles in impaired neuroplasticity and neuronal degeneration in Alzheimer''s disease, Parkinson''s disease, psychiatric disorders and stroke.