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Mitochondrial Oxidative Stress in Aging and Healthspan
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Additional evidence to support the association between autophagy and aging is shown by antiaging intervention studies (section Potential Interventions). Many interventions that have been shown to extend life span, including mammalian target of rapamycin (mTOR) inhibition by rapamycin49 or calorie restriction (CR)50 and Sirtuin activators51 are mediated through enhanced autophagy (Figure 21.3c).32,45,52–54 Similar to CR, inhibition of mTORC1 by rapamycin is well documented to extend life span in invertebrate models of aging, including flies,55 worms,56,57 and yeast,58,59 as well as in mice.49,60 In yeast and Drosophila, the life span extension by rapamycin was inhibited by deletion or silencing of Atg1, Atg7, or Atg5,53,54 indicating that enhanced autophagy is required for the life span extension benefit of mTORC1 inhibition. Sirtuins are class III histone deacetylases that deacetylate (activate) numerous transcription factors, cofactors, histones, and enzymes in response to metabolic stress using NAD+ as a cofactor. Dependent on cytoplasmic or mitochondrial NAD+, sirtuins act as a “sensor” protein for nutrition and energy balance.61,62 Sirtuins deacetylations of downstream pathways counteract the pathogenic mechanisms underlying aging and longevity as well as several age-related diseases, including diabetes, cardiovascular disease, cancer, inflammatory diseases, and neurodegenerative conditions.63 For example, Sirt1 has been shown to affect regulators of autophagy and many autophagy-related genes, including Atg5, Atg7, and Atg8.64 Sirt1 life span extension effect is also dependent on autophagy, as deletion of Beclin-1 (Atg6) which suppressed the induction of autophagy by Sirt, abolish its life span extension effect.52 Furthermore, several other interventions improving protein quality control have also been shown to improve health and aging in invertebrate and mammalian models.32,39,45,46
Autophagy regulation of ATG13 and ATG27 on biofilm formation and antifungal resistance in Candida albicans
Published in Biofouling, 2022
Siqi Liu, Liuliu Jiang, Haochen Miao, Ying Lv, Qinqin Zhang, Ming Ma, Wei Duan, Yun Huang, Xin Wei
In this study, knockdown of ATG13 and ATG27 reduced autophagic activity in C. albicans biofilm, as confirmed by ALP activity and AO-positive staining assays, as well as by TEM observation of autophagosomes in the mutant strains. In yeast, ATG13 is located at the center of the ATG1 kinase complex, including ATG1, ATG13, and the ATG17-ATG31-ATG29 subcomplex, which is a fundamental unit for autophagy initiation. Under nutrient-deficient conditions, ATG13 activates the ATG1 kinase complex through dephosphorylation of hyperphosphorylated ATG13 (Suzuki et al. 2015). ATG27 is a type I transmembrane protein that localizes to the pre-autophagosomal structure and other peripheral structures (Segarra et al. 2015), ATG13 potentially regulates autophagosome formation with the assistance of the transmembrane protein ATG27, which is important for the induction of autophagy in yeast. This study indicates that ATG13 and ATG27 regulate autophagy in C. albicans. The autophagosomes in the cells of atg13Δ/Δ and atg27Δ/Δ biofilms appear in irregular forms, and the autophagosome structures were unclear; once the formation of autophagosomes was disturbed, autophagic activity was reduced in these mutant strains.
The role of autophagy and mitophagy in cancers
Published in Archives of Physiology and Biochemistry, 2022
The discovery of autophagy genes (Atg) in yeast has led to a huge impact on our understanding of the mechanisms of the autophagy process. Most of the Atg genes are conserved in humans, and play various roles, including autophagy initiation, autophagosome formation and maturation (Thumm 2000, Hemelaar et al.2003). During initiation, Atg1 forms a complex with Unc-51 like kinase (ULK), which integrates inputs from mammalian target of rapamycin (MTOR) signalling (Mizushima et al.2011, Tanida 2011, Mizumura et al.2012). During autophagosome formation, Atg9 allows for membrane addition and retrieval to and from sites of autophagosome biogenesis (Mizushima et al.2008, 2011), while Atg6 (also known as Beclin1 in humans) forms a multimeric complex with Atg14, Vps15 and Vps34/PI3 kinase (Yang and Klionsky 2010). In addition to this, during autophagosome formation, Atg12 is activated by the enzyme Atg7 (E1-like ubiquitin ligase), which is subsequently transferred to Atg10 (E2-like ubiquitin ligase) to be conjugated to Atg5 (E3-like ubiquitin ligase), forming an autophagosomal precursor. Finally, Atg8 is required during the maturation phase (Ichimura et al.2000, Nemoto et al.2003). Some of the Atg proteins act as tumour suppressor genes. Epidemiological studies have revealed that genetic variants in Atgs might influence the biological function and prognosis of many cancers, including lung cancer, breast cancer, gastric cancer, head and neck squamous cell carcinoma, and renal cell carcinoma (Shen and Lin 2019).
Novel therapeutic strategies for stroke: The role of autophagy
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Seyed Fazel Nabavi, Antoni Sureda, Ana Sanches-Silva, Kasi Pandima Devi, Touqeer Ahmed, Momina Shahid, Eduardo Sobarzo-Sánchez, Marco Dacrema, Maria Daglia, Nady Braidy, Rosa Anna Vacca, Ioana Berindan-Neagoe, Diana Gulei, Davide Barreca, Maciej Banach, Seyed Mohammad Nabavi, Ahmad Reza Dehpour, Samira Shirooie
In yeast and mammals, stimuli like starvation, rapamycin, or hypoxia can induce the initiation phase, which is due to the inactivation of rapamycin complex 1 kinase (TORC1/mTORC1 in mammals) target [32]. On the contrary, insulin signaling activates the mTOR pathway and leads to the inhibition of autophagy. The aim of this phase is to induce the formation of the phagophore assembly site (PAS) for yeast or omegasome for mammals. The formation of the phagophore is well known in yeast where Atg9 plays a vital role in autophagosome formation. Atg9 cycles between the late endosome and trans-Golgi complex, presumably transporting sources for phagophore membrane elongation. Atg9 is retrieved from the pre-autophagosomal structure by the aid of Atg1, which is a serine/threonine protein kinase [33]. Atg1 initiates the autophagy cascade via protein–protein interaction with Atg13. Atg13 has a low affinity for Atg1 under normal conditions, however in a stressed state and after TORC1 inactivation, Atg13 is quickly dephosphorylated and interacts with Atg1 and the scaffold proteins, Atg11 and Atg17. The latter induces the formation of a second subcomplex with Atg29 and Atg31 [34,35]. The interaction between these two subcomplexes determines the formation of the PAS. In mammals, analogous proteins participate in this process, including two analogs of Atg1 called ULK-1 and ULK-2, as well as one analog of Atg17 called FIB200 [36].