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Mitochondrial Dysfunction in Huntington Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Md. Hafiz Uddin, Marufa Rumman, Tasnuva Sarowar
The lack of balance between mitochondrial fission and fusion negatively affects mitochondrial turnover. Autophagy, as previously referred, is an important intracellular mechanism that removes damaged organelles and misfolded/aggregated proteins to maintain cell homeostasis (Carvalho et al. 2015). Autophagy is characterized by the presence of autophagic vacuoles, autophagosomes (Kamat et al. 2014). An optimal level of autophagy is essential for recycling cellular organelles, which provides neuroprotection. However, increased autophagy is detrimental, causing neuronal degeneration (Kamat et al. 2014; Jing and Lim 2012; Wong and Cuervo 2010; Liu et al. 2009). Autophagy can be divided into two broad categories, namely, microautophagy and macroautophagy. In microautophagy, the lysosome directly engulfs intracellular smaller molecules and is independent of nutritional deprivation (Filosto et al. 2011). On the other hand, in macroautophagy, autophagosome is formed with intracellular larger molecules. This is then fused with the lysosome to generate autophagolysosome and undergoes subsequent degradation. Macroautophagy of mitochondria is termed as mitophagy [74,75].
Mitochondrial Oxidative Stress in Aging and Healthspan
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Several cellular mechanisms are involved in proteostasis and protein quality control. Autophagy is one of the main mechanisms degrading the vast majority of proteins. The other mechanism includes ubiquitin–proteasome pathway. Autophagic degradation involves lysosomes, which contains several digestive enzymes.39 Three major pathways have been described based on the delivery mechanisms of macromolecules to the lysosome: microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA).40 Microautophagy acts through invaginations of the lysosomal membrane directly engulfing cytoplasmic macromolecules into the lysosome followed by enzymatic degradation.40,41 Macroautophagy involves formation of autophagosomes, which are double-membrane vesicles formed by phagophores engulfing cytosolic proteins and organelles. These autophagosomes fuse with lysosomes, leading to the degradation of the sequestered cellular contents by lysosomal enzymes.42,43 CMA is a targeted degradation, in which cytosolic proteins containing a pentapeptide KFERQ motif are targeted and translocated across the lysosomal membrane, resulting in the degradation of specific proteins.44 These three mechanisms of autophagy may occur simultaneously in various cell types.39,45,46 Macroautophagy is the most extensively studied of these three mechanisms and will be the focus of the following discussion.
Novel approaches to targeted protein degradation technologies in drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Yu Xue, Andrew A. Bolinger, Jia Zhou
Microautophagy/autophagy regulates cellular homeostasis by degrading and recycling cytoplasmic components, such as protein aggregates, damaged organelles, and invading pathogens [2]. In 2019, Arimoto’s group first demonstrated the capability of cargo degradation by exploiting cellular autophagy machinery, which was termed as AUTAC [85]. AUTACs are heterobifunctional chimeras of a small cargo-targeting warhead linked to a guanine derivative tag that recruits the autophagy system. By conjugation, Halo tag (as a covalent warhead) with Cys-S-cGMP (as an autophagy tag), AUTACs were capable of selectively degrading enhanced green fluorescent protein (EGFP), which was mediated by autophagy receptor p62/SQSTM1. Several endogenous proteins, such as MetAP2, FKBP12, and BRD4, with different cargo ligands, were also selectively autophagically degraded by AUTACs 61–63. Furthermore, the mitochondria-targeted AUTAC 64 also enabled the mitophagy of fragmented mitochondria and the restoration of overall mitochondrial function, which may have beneficial effects in Down syndrome therapy.
Emerging roles of autophagy in the development and treatment of urothelial carcinoma of the bladder
Published in Expert Opinion on Therapeutic Targets, 2021
Pratishtha Gupta, Niraj Kumar, Minal Garg
Of the three variants of autophagy, macroautophagy is the best characterized pathway. It initiates with the formation of a double-membrane structure from the cell, called phagophore, and latter results in its development into autophagosome. This is followed by the engulfment of cellular components into autophagosomes for its delivery to lysosomes for fusion and degradation. Microautophagy is characterized by the continual autonomous change in the shape of the lysosome membrane upon direct engulfment of cytoplasmic components due to bulging or invagination [27]. The third variant of autophagy is identified as chaperone-mediated autophagy (CMA), where heat shock cognate 70 kDa protein, a cytosolic chaperone protein, recognizes the substrate proteins containing the specific KFERQ pentapeptide. Lysosome-associated membrane proteins (LAMPs) interact and direct lysosomal transport of cytosolic proteins/substrates for degradation and regulate CMA (Figure 2) [28,29].
Regulation of cytochrome P450 enzyme activity and expression by nitric oxide in the context of inflammatory disease
Published in Drug Metabolism Reviews, 2020
Edward T. Morgan, Cene Skubic, Choon-myung Lee, Kaja Blagotinšek Cokan, Damjana Rozman
In general, proteasomal degradation regulates the turnover of short-lived proteins, while the ALP regulates degradation of organelles and long-lived proteins (Schmid and Munz 2007; Ohsumi 2014). Proteins are delivered to the lysosomes by three mechanisms. In microautophagy, the cytosol is imported into the lysosomes via invagination of the lysosomal membrane. In chaperone-mediated autophagy, targeted proteins carry signal peptide tags, and cytosolic and lysosomal HSC70 chaperones assist the LAMP-2a transporter to import the protein cargo (Schmid and Munz 2007). Macroautophagy is the most common autophagic pathway, involving the engulfment of cytosolic constituents by a double membrane vesicle, the autophagosome (Ohsumi 2014). This fuses with lysosomes or late endosomes for degradation.