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  • br AURK Functions br Concluding


    AURK Functions
    Concluding Remarks The AURKs are crucial regulators of cell division; however, little is known about the mechanisms by which these kinases function in meiosis. Recent work has begun to chip away at the specific roles that each of the kinases play; however, as more is uncovered, additional questions arise. If AURKB and AURKC do have non-overlapping functions in meiosis, how are they differentially regulated? (see Outstanding Questions). One potential source of differential regulation could be proximity to substrates. Based on data from mitotic calculating dilution that express both AURKB and AURKC, they exist in separate complexes [77]. In addition, the kinases differ in catalytic activity levels, and AURKC, but not AURKB, is capable of binding to survivin, increasing its autophosphorylation [77]. While AURKB and AURKC are similar in sequence and structure, catalytic activity, stability, and binding partner affinity differences are likely key to their separate functions. It is tempting to hypothesize that one requirement for two independent CPC pools could act to restrict the amount of survivin available to bind AURKC, thus limiting its activity, because overexpression of AURKC results in atypical mitotic progression in cancer cells [111]. The high sequence similarity among the AURK family members has made discerning the individual kinase functions in meiosis challenging. Technical limitations in specifically targeting AURKB or AURKC using small-molecule inhibitors and compensatory abilities in single-knockout animals add to this challenge. Novel techniques will be necessary to discern the individual functions of these kinases in meiosis including methods to identify the endogenous localization of the kinases and targeted inhibition. Pinpointing the mechanism that restricts the isoforms to their respective signaling networks will be crucial for unraveling their complex functional regulation.
    Acknowledgments The authors apologize for not being able to cite all the primary work because of space limitations. The authors would like to thank Drs Cecilia Blengini and Suzanne Quartuccio for editorial comments. Work documented in this review was supported by grants from the National Institutes of Health (F31HD089591 to A.L.N.) and (R01GM112801-02 to K.S.).
    Macroautophagy, hereafter referred to as autophagy, is a highly regulated and conserved biological process. Induced during periods of nutrient deprivation, autophagy leads to the bulk degradation of cytoplasmic constituents, whose building blocks are used as an alternative energy supply. Furthermore, this catabolic process regulates the clearance of damaged organelles and long-lived proteins to ensure cellular homeostasis. The initiation phase of autophagy is characterized by formation of an isolation membrane, which engulfs selected cellular components. Upon expansion and membrane closure, the autophagosome fuses with the lysosome. Lysosomal hydrolases degrade the autophagosomal cargo and release the respective catabolites into the cytoplasm., Dysregulation of autophagy is involved in various pathological conditions, such as neurodegenerative disorders and cancer. However, by clearing malfunctioning organelles, as well as misfolded and aggregated proteins, autophagy significantly contributes to disease prevention., Damaged mitochondria for example can release reactive oxygen species, which have harmful effects on DNA and cellular macromolecules. Altered autophagy and dysfunctional mitochondria are frequently observed in patients that suffer from Parkinson’s disease. This prevents the selective degradation of mitochondria by autophagy, which is referred to as mitophagy. On the contrary, autophagy is regulated by ATP levels, which represent the available energy of a cell. Published findings postulate a connection between the inhibition of mitochondrial respiration and modulation of autophagy. Furthermore, altered mitochondrial respiration, especially complex I function, impairs autophagic flux. However, the exact mechanism that underlies this interplay is still unknown. Thus, the development of novel tool compounds, to investigate the connection between oxidative phosphorylation and autophagic flux is of utmost importance. Herein, we report the discovery of a novel, highly potent autophagy inhibitor termed Authipyrin, which targets mitochondrial complex I. Its potency and selectivity make it a useful tool to study the interplay between mitochondrial respiration and autophagy further.