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Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
Numerous proteins exhibited age-dependent variations in mouse brain, including 13 subunits of the mitochondrial electron transport chain complexes or ATPase, of which 10 were downregulated [89]. Of the 367 miRNAs studied, 70 showed significant age-dependent variations. Among them, 31 miRNAs exhibited consistent upregulation, and 17 were consistently downregulated with age. Of the 70 age-variable miRNAs, 27 targeted the 10 mitochondrial subunits that exhibited decreased expression in elderly animals. Among them, 16 miRNAs exhibited consistent upregulation with age, whereas 4 were consistently downregulated. These data show that multiple miRNAs are upregulated during normal aging. Expression levels of miR-22, -101a, -720, and -721 were inversely correlated with those of their predicted targets, Uqcrc2, Cox7a1, Atp5b, and Cox5b. Two main groups of miRNAs involved in aging could be discerned. The first consisted of crucial miRNAs that carry out tissue-specific targeting of genes, such as oxidative phosphorylation in the brain or detoxification in the liver, which leads to tissue-specific aging dysfunction. The other consisted of miRNAs that take part in regulating the common aging process. Thus, upregulated miRNAs miR-30d, -34a, -468, -669b, and -709 were found both in aging liver and brain, whereas miR-22, -101a, -720, and -721 were found specifically in aging brains, and miR-669c, -712, -214, and -93 were specific to aging livers. Interestingly, brains of the extremely old (33 months) mice had less upregulated miRNAs than those of 24-month-old mice. The proportion of mice surviving to 33 months of age being about 4%, one may suggest that these mice had a more stable epigenome, leading to reduced levels of deregulation of miRNA expression and extended life span.
Mitochondrial Dysfunction and Allergic Disease
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Kritika Khanna, Anurag Agrawal
Epidemiological studies have revealed maternal history of asthma and atopy as an important risk factor for development of allergies and asthma in children. Such an epidemiological link along with the exclusive transmission of mitochondria from the maternal lineage indicates the role of mitochondrial genome sequence variations in atopic diseases. Indeed, initial reports of associations between mitochondria and atopy show a genetic link between the two. Common mitochondrial haplogroup U has been shown to be significantly associated with total serum IgE levels. This haplogroup also showed trends of associations with greater skin prick reactivity and higher incidence of atopic dermatitis (Raby et al. 2007). Another study demonstrates haplogroup in D loop region of the mitochondrial DNA to be associated with cow milk allergy expressed as atopic dermatitis and gastrointestinal disease (Muino et al. 2014). Apart from genetic associations, many functional studies have highlighted the role of mitochondria dysfunction in allergic diseases. The bronchial epithelium of the human asthma subjects has been demonstrated to have swollen mitochondrial morphology (Konrádová et al. 1985). Such ultrastructural changes, with respect to loss of cristae and mitochondrial swelling, were also observed in murine model of allergic inflammation. This was associated with reduced expression of cytochrome c oxidase and mitochondrial respiratory complex I in the bronchial epithelium and increased cytochrome c in the lung cytosols (Mabalirajan and Ghosh 2013). In another study, Aguilera et al. demonstrated that pre-existing mitochondrial defects can aggravate allergic airway inflammation. Exposure of airway epithelial cells to ragweed pollen extract was shown to induce oxidative damage to the mitochondrial respiratory chain complex proteins. Among these proteins, destruction of the ubiquinol-cytochrome c reductase core protein II (UQCRC2), which is an important structural protein of the complex III of the mitochondrial respiratory chain, was found to increase mitochondrial ROS generation. Interestingly, siRNA mediated downregulation of the core protein in mice, prior to exposure of ragweed pollen, led to aggravated allergic responses in terms of bronchial hyper-responsiveness, increased eosinophil recruitment and elevated mucin production in the airways. Thus, any such pre-existing defects in the mitochondrial respiratory chain can lead to an enhanced allergic response to ragweed pollen (Aguilera-Aguirre et al. 2009). These observations also have important implications on the environmental factor associated exacerbation of allergies and atopy. Oxidant environmental pollutants like diesel exhaust particles, ozone, tobacco smoke particles and factors like respiratory virus infections, can induce mitochondrial dysfunction which could further aggravate the allergic symptoms in atopic individuals.
Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome
Published in OncoImmunology, 2020
Shaokang Ma, Jonathan Chee, Vanessa S. Fear, Catherine A. Forbes, Louis Boon, Ian M. Dick, Bruce W. S. Robinson, Jenette Creaney
CD8+ T cells typically respond to 8-11mer short peptide epitopes in an ELISPOT assay, whereas both CD4+ and CD8+ T cells can respond to 27mer long peptides in an ELISPOT assay with antigen-presenting cells.32 To further explore responses to our neo-antigen candidates, we tested long peptides encoding the top nine expressed neo-antigen candidates (listed in Supplementary table III). Responses to mutant UQCRC2 long peptide were again detected and seen in both untreated and treated mice (Figure 3d, e). We detected immune responses to an additional neo-antigen, mutant UNC-45 homolog A (UNC45a) in the dLN of treated animals, but not untreated animals (Figures 3e and g). All other neo-antigen long peptides failed to elicit any IFNγ production regardless of treatment. Thus ICPB unmasked one additional neo-antigen rather than many as we had hypothesized.
The mitophagosome, a novel ultrastructure of mitophagy in the alcoholic steatohepatitis mouse model: a transmission electron microscope study
Published in Ultrastructural Pathology, 2022
Yanfei Lang, Xiaxia Zhang, Xin Li, Youqing Xu
There is currently limited research on mechanisms involving mitophagy in alcoholic liver disease, and especially regarding its ultrastructural features. Zhou, et al. showed that ethanol-feeding induced the formation of a necroptotic signaling loop and high-expression of ubiquinol-cytochrome c reductase core protein 2 (UQCRC2), which triggered mitophagy signals.23 Zhao et al. suggested that chronic alcohol consumption stimulated the PTEN induced kinase 1 (PINK1) and Parkin-associated mitophagy signals.24 Lu et al. confirmed that the regulation of AMP-activated protein kinase (AMPK) and UQCRC2 is a significant factor in mitophagy.25 Eid et al. using the unique short-term acute-on-chronic alcohol-feeding model, indicated that after 10 weeks of alcohol feeding, significant numbers of large autophagic vacuoles formed, whose main components were mitochondria and lipid droplets, which existed in the form of encapsulation.26 Yu et al. suggested that rats fed a Lieber-Decarli diet containing 5% ethanol for 15 weeks led to significant mitophagy, which is also a means of encapsulation.27 In contrast, our study is based on a shorter 3-week alcohol-feeding model, showed direct fusion occurs, which may represent a cellular mechanism that avoids excessive energy and nutrient consumption to a greater degree. Furthermore, there are limitations to the previous techniques used to detect cellular ultrastructures. Compared to light microscopy, TEM can display the ultrastructure of the nanometer scale more clearly and provides more information on individual cellular components. Nonetheless, due to the lack of experienced personnel, the TEM technique has not been widely adopted or used in clinical practice.
Circ-UQCRC2 aggravates lipopolysaccharide-induced injury in human bronchial epithelioid cells via targeting miR-495-3p/MYD88-mediated inflammatory response and oxidative stress
Published in Autoimmunity, 2021
Xuan Zhang, Chunbao Chen, Bei Li, Wei Lu
In our study, LPS-induced 16HBE cells were used as a pneumonia cell model. We first analyzed the role of circ-UQCRC2 in pneumonia through loss-of-function experiments. Subsequently, bioinformatics analysis was used to predict the downstream targets of circ-UQCRC2, and the working mechanism was verified by functional experiments.