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Mechanisms of Nanotoxicity to Cells, Animals, and Humans
Published in Vineet Kumar, Nandita Dasgupta, Shivendu Ranjan, Nanotoxicology, 2018
Belinda Wong Shu Ee, Puja Khanna, Ng Cheng Teng, Baeg Gyeong Hun
One of the possible mechanisms underlying nanoparticle-mediated ROS production is the impairment of ETC which leads to the depolarization of the inner mitochondrial membrane. Impaired mitochondria can be selectively degraded by a selective autophagy process known as mitophagy (Priault et al. 2005). Oxidative stress leads to autophagy by oxidizing a cysteine residue on Atg4, thus disrupting its protease activity. This directly promotes the lipidation of LC3 and autophagy (Scherz-Shouval et al. 2007). TiO2 NP-mediated oxidative stress in human cerebral endothelial cells (HCECs) led to autophagy via this mechanism, as characterized by an increase in LC3 levels and autophagosome formation (Halamoda Kenzaoui et al. 2012). SiNPs exposure also induced an elevation in ROS and L3 levels in MRC-5 and HepG2 cells, indicating the activation of autophagy machinery (Yu et al. 2014; Petrache Voicu et al. 2015). Furthermore, PAMAM was found to induce oxidative stress and Akt/mTOR-mediated autophagy in PC12 cells (Li et al. 2015). There are various pathways utilized by nanoparticles to activate autophagy in a cell. One of the most prominent pathways is the mTOR pathway. Similarly, oxidative stress generated by nanoparticles can also act as a trigger for autophagy activation. When cells fail to eliminate foreign substances via autophagy, they undergo apoptotic processes and programmed cell death.
Nanoparticles and Viruses as Mitophagy Inducers in Immune Cells
Published in Bertrand Henri Rihn, Biomedical Application of Nanoparticles, 2017
Housam Eidi, Zahra Doumandji, Lucija Tomljenovic, Bertrand Henri Rihn
Mitochondria are considered the chief source of intracellular ROS production because mitochondrial ROS (mROS) have been directly linked to multiple physiological processes including immunity, differentiation, autophagy, and metabolic adaptation (Sena and Chandel 2012). The removal of damaged or excessive mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathways or the mitophagic receptors Nix and Bnip3 (Ding and Yin 2012; Figure 6.9). Some viruses induce mitophagy (Kim, Khan et al. 2013, Kim, Syed et al. 2013). Studies suggest that this strategy might provide a replicative advantage for the virus against development of antiviral immune responses by the host (Xia et al. 2014). Indeed, viruses exploit the mitophagy pathway in order to increase mithophagy and thereby increase their replication (Xia et al. 2014). Also, some viruses can generate ROS via their oncogenic products: For example, the hepatitis B virus (HBV) X protein (HBx); hepatitis C virus (HCV) core, E1 and NS3; human papillomavirus 18 (HPV-18) E2; and the human T-cell leukemia virus 1 (HTLV-1) p13 and Tax (Dizdaroglu 1992, Lu et al. 2001, Demple and Harrison 1994). As viruses, NPs produce ROS causing mitochondrial damage which involves the disruption of the breathing chain and the formation of more ROS. Thus, damaged mitochondria will be degraded by mitophagy and the process of autophagy is put in place (Luo and Rubinsztein 2007, Yu et al. 2013).
Stem Cells for Parkinson’s Disease
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Two mutations strongly associated with early onset PD include those in PINK1 and PARK2. PINK1 proteins play an important role in the recruitment of PARKIN protein, which is encoded by PARK2 at sites of mitochondrial damage. PARKIN is an E3 ubiquitin ligase which plays a critical role in mitophagy by ubiquitinating various mitochondrial proteins thereby promoting their degradation. iPSC lines have been generated from patients containing PINK1 missense mutation (60). Upon dopaminergic neuronal differentiation, they found that the cells expressed lower levels of PINK1 compared to healthy controls. The cells were then exposed to drugs promoting mitochondrial depolarization and damage. In the patient lines, interestingly, PARKIN failed to get recruited to sites of mitochondrial damage. The phenotype could then be rescued by viral-mediated overexpression of normal PINK1 protein in the cells. Similar studies were also carried out by the Klein lab (61). They compared Parkinson phenotypes in the patient fibroblasts and the iPSC-derived neurons. They interestingly discovered that patient lines had variable response such that they concluded that mitophagy differs between fibroblasts and neuronal cells and also between native and overexpressed PARKIN in vitro systems. Similarly, another study using PINK1 mutant lines from patients looked at mitochondrial dysfunction in original fibroblasts and in the iPSC-derived neurons (58). PINK1 iPSC-derived neurons exhibit lowered production of reduced GSH synthase upon exposure to either valinomycin or concanamycin, drugs which trigger mitochondrial depolarization, compared to control lines. Additionally, the treatment resulted in increased levels of ROS production in PINK1 iPSC-derived neurons but not in controls. The data confirmed the original ideas of increased susceptibility of dopaminergic neurons in Parkinson’s patients to ROS. The group then sought to test compounds or drugs that may potentially rescue the phenotype. They found that exposure to rapamycin and GW5074, a LRRK2 inhibitor, prior to drug exposure, could reduce ROS production in the patient lines. Similarly, another antioxidant, Coenzyme Q, was neuroprotective in these cultures.
A review of microalgal cell wall composition and degradation to enhance the recovery of biomolecules for biofuel production
Published in Biofuels, 2023
Syafiqah Md Nadzir, Norjan Yusof, Norazela Nordin, Azlan Kamari, Mohd Zulkhairi Mohd Yusoff
In contrast, paraptosis is a non-apoptotic form of PCD accompanied by endoplasmic reticulum and mitochondrial dilation, chromatin spotting without DNA fragmentation, significant cytoplasmic swelling and vacuolation, and alternative caspase activation [127]. It is mediated by mitogen-activated protein kinases and differs significantly from apoptosis due to the absence of caspase activity [128]. Another non-apoptotic form of PCD, depending on the presence of iron, is ferroptosis. It is associated with lipid peroxidation and accumulation of ROS [129]. Iron molecules induce harmful lipid accumulation by ROS, which is mediated by inhibition of cysteine import and glutathione depletion [130]. Autophagy, in contrast, is a type of PCD marked by a rise in the number of autophagosomes, autolysosomes, and small lytic vacuoles. It is a catabolic process induced by the autophagy gene (atg) that degrades long-lived organelles and proteins. Autophagy can be used to selectively degrade organelles such as mitochondria (mitophagy) and ribosomes (ribophagy), as well as misfolded and aggregated proteins [131,132]. The early stage of autophagy consists of the induction and formation of autophagosomes, whereas the late stage includes the fusion of autophagosomes and lysosomes, followed by degradation of the fusion complex and reformation of lysosomes [133].
Effects of mild running on substantia nigra during early neurodegeneration
Published in Journal of Sports Sciences, 2018
Michael F. Almeida, Carolliny M. Silva, Rodrigo S. Chaves, Nathan C. R. Lima, Renato S. Almeida, Karla P. Melo, Marilene Demasi, Tiago Fernandes, Edilamar M. Oliveira, Luis E. S. Netto, Sandra M. Cardoso, Merari F. R. Ferrari
Mitophagy dysfunction during early neurodegeneration is associated with increased oxidative stress, since mitochondria are the primary source of reactive oxygen species (Palikaras & Tavernarakis, 2012). In the present study, an increased production of H2O2 was observed, which correlated with mitochondria accumulation. Moderate physical activity prevented the increase of H2O2 and did not change the activity of antioxidant enzymes. Decrease of GR activity may be result of unchanged of GSH activity, decreasing the substrate GSSH for GR. This strengths the hypothesis that H2O2 was mainly produced by dysfunctional mitochondria, which was re-established by moderate physical activity.