Mitochondrial Oxidative Stress in Aging and Healthspan
Shamim I. Ahmad in 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.
Apoptosis and Cell Death
John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie in Basic Sciences Endocrine Surgery Rhinology, 2018
Macroautophagy is a process by which cytoplasm and organelles are engulfed into double membrane bound vesicles called autophagosomes (self-eating), which ultimately fuse with lysosomes for digestion and recycling of contents by lysosomal hydrolases. This process is utilized, for example, in situations of starvation, oxidative stress or hypoxia. Publications frequently specify that it is macroautophagy that is the form of autophagy being referred to (i.e. the use of autophagosomes to transport cargo to the lysosome) and then simply use the term ‘autophagy’ thereafter. Tumour cells are believed to utilize this process, promoting survival of tumour cells in unfavourable conditions. Autophagy contributes to chemotherapy resistance, for example in esophageal cancer cells treated with cisplatin or 5-fluorouracil.14 Some agents can induce excessive autophagy leading to cell death, but the consequence of autophagy can be context dependent and the microenvironment can adjust the threshold at which autophagy levels promote cell survival or cell death. There is now believed to be cross-talk between the processes of apoptosis, autophagy and ‘regulated/programmed necrosis’.15
Mitochondrial Dysfunction in Huntington Disease
Abhai Kumar, Debasis Bagchi in Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
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].
Anti-tumor immunity influences cancer cell reliance upon ATG7
Published in OncoImmunology, 2020
Michael D. Arensman, Xiaoran S. Yang, Wenyan Zhong, Stephanie Bisulco, Erik Upeslacis, Edward C. Rosfjord, Shibing Deng, Robert T. Abraham, Christina H. Eng
Macroautophagy (herein referred to as autophagy) is a cellular maintenance and survival mechanism that traffics cytosolic components to lysosomes for degradation and recycling via double-membraned vesicles termed autophagosomes. The ATG7 protein is essential for autophagy,1 as its ubiquitin E1-like activity facilitates the conjugation of ATG5 to ATG12 and of phosphatidylethanolamine (PE) to LC3-I (MAP1LC3B cleaved by ATG4 enzymes), generating the lipidated form LC3-II. This event leads to the loading of autophagic cargo and cargo receptors, such as p62/SQSTM1, to autophagosomes and subsequent degradation in lysosomes.2 Basal levels of autophagy maintain cellular homeostasis by limiting the accumulation of damaged proteins and organelles, and autophagy can be upregulated upon nutrient deprivation in order to maintain essential intracellular metabolite levels.3
Autoantibodies against the autophagic protein microtubule-associated light-chain 3 (LC3): Immunocharacterization of an atypical ANA pattern
Published in Autoimmunity, 2020
Emilia Maellaro, Lucia Terzuoli, Maria Romana Bacarelli, Barbara Del Bello, Nicola Bizzaro, Brunetta Porcelli
Macroautophagy (commonly and hereafter referred to as autophagy) is a physiologically controlled auto-digestion process (present virtually in all cell types) through which cytoplasmic organelles and macromolecules are sequestered in double-membrane autophagosomes and subsequently degraded following lysosomal fusion. This catabolic process, by recycling components no longer functional, contributes to maintain cellular homeostasis and acts as a survival mechanism in different stress conditions [6,7]. In the complex autophagic machinery, a key step is initiated by Atg4 (autophagy-related protein 4)-mediated processing of pro-LC3 to mature LC3-I, which is in turn conjugated to phosphatidylethanolamine of the autophagosomal membranes; such conversion to the lipidated form, LC3-II, is crucial for elongation of these membranes and for assisting autophagosomal vesicle maturation [6].
When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies
Published in Expert Review of Proteomics, 2018
Julie A. Reisz, Alexander S. Barrett, Travis Nemkov, Kirk C. Hansen, Angelo D’Alessandro
The lysosomal-autophagy pathway targets misfolded proteins, ubiquitinated proteins, and larger molecular structures, such as aggresomes and even damaged organelles. There exist several types: chaperone-mediated authophagy (CMA), microautophagy, and macroautophagy. In CMA, protein chaperones assist in recognition of damaged cytosolic proteins bearing the KFERQ motif and translocation to the lysosome surface, where they bind to protein Lamp2a and transported into the lysosome for degradation. CMA requires the sophisticated coordination and cross talk of many proteins; these essential molecular interactions have been recently reviewed in detail [61]. Microautophagy involves direct lysosomal absorption of smaller cellular debris, whereas macroautophagy, the dominant form referred to as simply ‘autophagy,’ requires the synthesis of a double membrane around the damaged molecules to form an autophagosome that is later engulfed by the lysosome. The lysosome contains at least 60 unique hydrolase enzymes [62] and maintains an acidic pH of 4.5–5 for proteolysis through the proton pump activity of vacuolar-type H+-ATPases (V-ATPases). As such, chemical integrity of the lysosome is reliant on an adequate ATP supply.
Related Knowledge Centers
- Autophagosome
- Cytoplasm
- Secretion
- Vesicle
- Lysosome
- Homeostasis
- Microautophagy
- Chaperone-Mediated Autophagy
- Glucagon
- Mitochondrion