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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.
Mapping the human sperm proteome – novel insights into reproductive research
Published in Expert Review of Proteomics, 2023
Mika Alexia Miyazaki, Raquel Lozano Guilharducci, Paula Intasqui, Ricardo Pimenta Bertolla
LC-MS/MS data were utilized to perform an in silico analysis to identify mitochondrial DEPs comparing varicocele infertile men with fertile healthy donors. The identified proteins were confirmed by western blot analysis and it was demonstrated that proteins such as LTM1, EF-hand domain-containing protein (EFHC), MICOS complex subunit MIC60 (MIC60), PGAM5, Isochorismatase domain-containing protein 2 (ISOC2) and Mitochondrial import receptor subunit TOM22 homolog (TOM22), related to mitochondrial structure, and NDUSF1, cytochrome b-c1 complex subunit 2, mitochondrial (UQCRC2), COX5B and the core enzymes of carbohydrate and lipid metabolism, related to mitochondrial function, were downregulated in the varicocele group. The impaired mitochondrial function was associated with the low expression of Sodium/potassium-transporting ATPase subunit alpha-4 (ATP1A4), HSPA2, Sperm surface protein Sp17 (SPA17) and Apolipoprotein A-I (APOA1), responsible for an adequate sperm function. The impairment of these pathways leads to an increase of reactive oxygen species (ROS) and a decrease of ATP production. The authors suggested the use of NDUSF1, UQCRC2, and COX5B as noninvasive biomarkers of altered sperm function in patients with varicocele, which may assist in the development of a mitochondria-targeted approach to treat varicocele [91]
Mitochondrial dysfunction in Alzheimer’s disease - a proteomics perspective
Published in Expert Review of Proteomics, 2021
Morteza Abyadeh, Vivek Gupta, Nitin Chitranshi, Veer Gupta, Yunqi Wu, Danit Saks, Roshana Wander Wall, Matthew J. Fitzhenry, Devaraj Basavarajappa, Yuyi You, Ghasem H Salekdeh, Paul a Haynes, Stuart L Graham, Mehdi Mirzaei
More recently, Adav and colleagues (2019) studied the brain proteome of the medial frontal gyrus of AD patients and healthy controls, the global proteome observations were cross-validated using label-free proteomics analysis of isolated brain mitochondria. Overall, 434 mitochondrial proteins were identified; of those, 208 proteins were differentially expressed in AD patients, which were mainly related to ETC and ATP-synthase, and most were complex I components. Interestingly, three complex I proteins were specifically down-regulated in mitochondria of early AD onset samples, including: Cytochrome c oxidase subunit NDUFA4 (NDUFA4); NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial (NDUFA9); and Acyl carrier protein, mitochondrial (NDUFAB1). These proteins are involved in stabilizing the junction between membrane and matrix arms of complex I. Consequently, their down-regulation indicates a gradual destabilization of this junction in early AD pathogenesis [77,78]. Moreover, down-regulation of cytochrome c oxidase subunits (COX5A, COX5B COX7A2, COX7A2L) and cytochrome c1 mitochondrial heme protein, (CYC1) in late onset AD brain demonstrated depleted energy production, which is a key biochemical characteristic of the disease progression. Cumulative results from the study indicated the dysfunctional mitochondrial complexes as being instrumental in AD pathogenesis in the early stages [78]. More interestingly, Se-methylselenocysteine (SMC) has been suggested to play a role in ameliorating neuropathology and cognitive deficits associated with 3xTg-AD mice by Du and colleagues (2021). This study showed that SMC treatment can modulate the expression of mitochondrial related proteins advocating that early stage intervention can potentially reverse the pathology underlying AD progression [79].
Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing
Published in OncoImmunology, 2022
Wen-Sa Peng, Xin Zhou, Wen-Bin Yan, Yu-Jiao Li, Cheng-Run Du, Xiao-Shen Wang, Chun-Ying Shen, Qi-Feng Wang, Hong-Mei Ying, Xue-Guan Lu, Ting-Ting Xu, Chao-Su Hu
A PPI network was constructed using the STRING database to reveal the interactions between the DEGs upregulated in rNPC. Using the MCODE in Cytoscape, three modules that might play important roles in the characteristics of rNPC were detected (Figure 5F). Module 1 correlated with antigen presentation, consisting of both MHC-I (HLA-A/B/C/E/F) and MHC-II (HLA-DQ/DP/DR) molecules. Upregulation of these genes in rNPC indicated decreased tumor immune escape and increased T cell recognition/activation, which further confirmed increased immunogenicity of rNPC cancer cells. Module 2 consisted of KRT genes encoding keratins, which are the typical intermediate filament proteins of the epithelium. KRT6/16/17 are constitutive keratins with a relatively high proliferative state and are induced upon stress, injury, or inflammation. KRT5 is commonly used to diagnose undifferentiated NPCs.43 This module showed an altered epithelial differentiation state in patients with the complicated epithelial cell development process. Module 3 consisted of enzymes responsible for ATP synthesis (ATP5L/ATP5F1/ATP5H/ATP5G3) and the mitochondrial respiratory chain (COX5B/COX7B/COX4I1 and UQCRB/UQCRQ), consistent with increased oxidative phosphorylation (OXPHOS) and hypoxia in rNPC. With high metastatic and tumorigenic potential, cancer stem cells are more reliant on OXPHOS than the bulk and putatively nonstem components.44 Thus, OXPHOS inhibitors could be used to target rNPC and alleviate therapeutically adverse tumor hypoxia. Apart from the hub genes listed, the heatmap of DEGs showed that some immune-related genes, such as chemokines (CXCL1, CXCL8, CXCL14, and CCL20) and inhibitors (IDO1), were highly expressed in rNPC, indicating a complex immune response of these cancer cells (Figure S4E).