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Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
Mitochondrial stress induces cellular senescence, also referred to as mitochondrial dysfunction-associated senescence (MiDAS) (Wiley et al. 2016). Mitochondrial stress due to oxidative damage decreases the total number of functional mitochondria or impair function of the mitochondrial electron transport chain (ETC), resulting in decreased ATP production and reduced mitochondrial function (Nicolson 2014). Inhibition of mitochondrial electron transport complex I by rotenone causes cellular aging in normal human fibroblasts and primary mouse cells (Miwa et al. 2014; Moiseeva et al. 2009). Inhibition of complex II activity by down-regulating expression of iron-sulfur subunit also promotes premature senescence (Yoon et al. 2003). Likewise, exposure to the complex III inhibitor antimycin A and the complex V inhibitor oligomycin A are linked to cellular senescence, as observed by up-regulation of p16, p21, and p27- CDK inhibitors (CDKIs) (Stöckl et al. 2006). Knockdown of the Rieske iron sulfur protein (RISP), which transfers electrons from ubiquinol to cytochrome c1 in complex III of the ETC, also triggers the senescence phenotype (Moiseeva et al. 2009).
Oxidative Stress and the Aging Brain: From Theory to Prevention
Published in David R. Riddle, Brain Aging, 2007
Carmelina Gemma, Jennifer Vila, Adam Bachstetter, Paula C. Bickford
Mitochondria are the main source of ROS [11, 12]. The generation of mitochondrial ROS is a consequence of oxidative phosphorylation, a process that occurs in the inner mitochondrial membrane and involves the oxidation of NADH to produce energy. This energy is then used to phosphorylate ADP. Mitochondrial electron transport involves four-electron reduction of O2 to H2O: NADH and succinate donate electrons respectively to complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase) of the mitochondrial electron transport chain. Coenzyme Q accepts electrons from Complexes I and II, and next donates electrons to cytochrome b in complex III (ubiquinone-cytochrome c reductase). In complex III, the electrons are donated to cytochrome c1, and so to cytochrome c, to complex IV (cytochrome c oxidase), which finally reduces O2 to H2O. However, during mitochondrial electron transport, a one-electron reduction of O2 results in O2−•. Studies on isolated mitochondria in the presence of a high, nonphysiological concentration of oxygen estimated that mitochondria convert 1 to 2% of the oxygen molecules consumed into O2−• [13], but subsequent investigations under more physiological conditions reduced this value to 0.2% [14, 15]. Superoxide anion is detoxified by the mitochondrial mangansese (Mn) superoxide dismutase (MnSOD) to yield hydrogen peroxide (H2O2), and the H2O2 is then converted to H2O by catalase. H2O2 in the presence of reduced transition metals can also be converted to hydroxyl radical (OH−). Each of these by-products is a potential source of oxidative damage to the mitochondria, cellular proteins, lipids, and nucleic acids.
Proteomic characterisation of leech microglia extracellular vesicles (EVs): comparison between differential ultracentrifugation and Optiprep™ density gradient isolation
Published in Journal of Extracellular Vesicles, 2019
T Arab, A Raffo-Romero, C Van Camp, Q Lemaire, F Le Marrec-Croq, F Drago, S Aboulouard, C Slomianny, A-S Lacoste, I Guigon, H Touzet, M Salzet, I Fournier, C Lefebvre, J Vizioli, P-E Sautière
We identified 354 proteins in UC sample, 242 of which overlapping with the ODG EV-rich fractions F4 to F6. Between the 112 UC-specific proteins, we did not detect well-known molecules associated with the EVs. These proteins belong to several cellular component including nucleus, cytosol and cytoplasm (histones family members, apolipoproteins, caspases, actin, tubulin and calcium/calmodulin dependent protein kinase II family members, NADH subunits, cytochrome C1…). Notably, after the density gradient treatment of the EV pellet these proteins spread in ODG EV-poor fractions F1, F2, F3, F7 and F8 (Figure 4(a)). However, the presence of few subtypes of EVs outside of F4, F5 or F6 cannot be excluded e.g. in the lightest fraction F1 or alternatively in the densest fraction F8. Our methods to enrich these subtypes should be adapted in order to recover and characterise enough EVs to test their potential activity [65]. These data confirm the interest of the ODG protocol in removing EVs protein contaminants. NTA observations and MS analyses indicated that differential UC did not selectively enrich the sample for EVs proteins but also induced co-isolation of contaminating factors. Some proteins (e.g. actin, GAPDH, HSP family proteins) from the ExoCarta top100 list (Table 1) were identified in all the ODG fractions (F1 to F8). However, these molecules are not strictly EV-specific but may belong to other cellular components and could be involved in different cellular processes/pathways. This is why to assess strictly the presence of EV markers further studies should be performed to establish their precise cellular topology [26].
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].
Quantitative analysis of the global proteome in lung from mice with blast injury
Published in Experimental Lung Research, 2020
Ying Liu, Yunen Liu, Changci Tong, Peifang Cong, Xiuyun Shi, Lin Shi, Mingxiao Hou, Hongxu Jin, Yongli Bao
According to our results, ROS and oxidative damage were detected in blast-injury mice. ROS are produced in mitochondria as a by-product of ATP production through oxidative phosphorylation. To our excitement, oxidative phosphorylation was also significantly enriched in the blast-injury mice according to proteomics analysis. Therefore, we detected the protein changes of oxidative phosphorylation in depth mechanism research.16,17 Our studies revealed the changes of oxidative phosphorylation including the NADH dehydrogenase, F-type ATPase, Cytochrome C reductase and Cytochrome C in the lung of blast-injury mice. Using Western blotting, we confirmed the change of several proteins, such as NDUFV1, NDUFA4, NDUFB3, NDUFB5, NDUFB6, and COX. Oxidative phosphorylation occurs in the inner mitochondrial membrane.18 It is the coupling reaction that utilizes substrates derived from glucose, fatty acids, and amino acids to produce ATP, which is a main source of organism energy.19 The enzymes of the oxidative phosphorylation consist of different protein complexes; The function is to carry out electron transfer, H transfer, oxygen utilization, and produce H2O and ATP.20 Complex I is NADH-Q reductase; Complex II is succinic acid-Q reductase; Complex III is cytochrome reductase; Complex IV is cytochrome oxidase; Complex V is ATP synthase.21 In this study, NDUFV1, NDUFA4, NDUFB3, NDUFB5, NDUFB6 all belong to NADH dehydrogenase. Ndufv gene relevant to mitochondrial respiration. It is reported that the NADH-dependent generation of extracellular superoxide was prevented by knockdown of NDUFV.22 Cyt1 belongs to cytochrome c reductase. Cytochrome c reductase exists as a dimer, each monomer contains two cytochrome b(b562、b566), a cytochrome c1 and an iron-sulfur protein. The founction is to catalyze electron transfer from coenzyme Q to cytochrome c.23 COX belongs to cytochrome c oxidase. Cytochrome c oxidase is an enzyme at the end of the mitochondrial respiratory chain, it take part in the electron transport in the mitochondrial respiratory chain and be related to the production of reactive oxygen species.24 For each pair of electrons transferred, four protons are simultaneously pumped from the mitochondrial matrix to the membrane gap.25 ATP synthase is widely distributed in the inner membrane of mitochondria and participates in the ATP generation.26 The electron transfer to proton pumping across the mitochondrial inner membrane to generate a transmembrane electrochemical potential and interferes with energy metabolism.27 Furthermore, it is reported that the alterations in oxidative phosphorylation can be related to the change of oxidative stress and inflammatory processes.28 The respiratory chain complex I and complex III are the sites of ROS generation during oxidative phosphorylation.29 These are consist with our finding in blast-injury mice.