Preface—Autophagy: An old mechanism with new challenges ahead

Martinez, Aitziber Buqué; Galluzzi, Lorenzo

doi:10.1016/s1877-1173(20)30092-2

Cited by 3 publications

(2 citation statements)

References 50 publications

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“…Like other processes, autophagy plays a central role in maintaining the proteome integrity of the cell. Autophagy comprises distinct stages, beginning with initiation/nucleation and followed by elongation, maturation, and lysosomal fusion, resulting in the degradation of autophagic cargo [177]. A complex containing VPS34, BECLIN1, ATG14, VPS15, and AMBRA1 controls nucleation by phosphorylating the membrane-associated phosphoinositol lipids (PI), resulting in the accumulation of phosphoinositol-3-phosphates (PI3Ps) on the cytoplasmic surface of organelle membranes [178].…”

Section: Autophagymentioning

confidence: 99%

MicroRNAs in Age-Related Proteostasis and Stress Responses

Matai

Slack

2023

ncRNA

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Aging is associated with the accumulation of damaged and misfolded proteins through a decline in the protein homeostasis (proteostasis) machinery, leading to various age-associated protein misfolding diseases such as Huntington’s or Parkinson’s. The efficiency of cellular stress response pathways also weakens with age, further contributing to the failure to maintain proteostasis. MicroRNAs (miRNAs or miRs) are a class of small, non-coding RNAs (ncRNAs) that bind target messenger RNAs at their 3′UTR, resulting in the post-transcriptional repression of gene expression. From the discovery of aging roles for lin-4 in C. elegans, the role of numerous miRNAs in controlling the aging process has been uncovered in different organisms. Recent studies have also shown that miRNAs regulate different components of proteostasis machinery as well as cellular response pathways to proteotoxic stress, some of which are very important during aging or in age-related pathologies. Here, we present a review of these findings, highlighting the role of individual miRNAs in age-associated protein folding and degradation across different organisms. We also broadly summarize the relationships between miRNAs and organelle-specific stress response pathways during aging and in various age-associated diseases.

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Section: Autophagymentioning

confidence: 99%

MicroRNAs in Age-Related Proteostasis and Stress Responses

Matai

Slack

2023

ncRNA

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“…Despite other variations like microautophagy and chaperone-mediated autophagy ( CMA ) being prevalent in cellular housekeeping— macroautophagy is the most common and is interchangeably used with 'autophagy.' Autophagy comprises distinct stages, starting with induction (ULK complex), and followed in order by vesicle nucleation (BECLIN-1, UVRAG, RAB5A), elongation (LC3B, ATGs4, 7, 5, 12, 16, 16L1, 10A), retrieval (ATGs2B, 9A), lysosomal fusion (LAMP2A), and finally degradation of the autophagic 'cargo' (SQSTM1/P62) [ 7 ]. While it is commonly initiated during stress conditions (infection, radiation, hypoxia), it is also well established that regulation of autophagy is a crucial checkpoint in cancer, viral infection [ 20 ], lung disease [ 61 ], innate immunity [ 55 ], kidney disease [ 6 ], diabetes, obesity, osteoarthritis [ 48 ], inflammation-related disorders [ 18 ], cardiovascular disease [ 1 ], aging-related disease, lysosomal storage disorders, and neurodegeneration [ 63 , 64 , 99 ].…”

Section: Introduction—autophagy and Mirnasmentioning

confidence: 99%

Regulation of autophagy by miRNAs in human diseases

Roy

2021

Nucleus

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Autophagy is a homeostatic process designed to eliminate dysfunctional and aging organelles and misfolded proteins through a well-concerted pathway, starting with forming a double-membrane vesicle and culminating in the lysosomal degradation of the cargo enclosed inside the mature vesicle. As a vital sentry of cellular health, autophagy is regulated in every human disease condition and is an essential target for non-coding RNAs like microRNAs (miRNAs). miRNAs are short oligonucleotides that specifically bind to the 3'-untranslated region (UTR) of target mRNAs, thus leading to mRNA silencing, degradation, or translation blockage. This review summarizes the recent findings regarding the regulation of autophagy and autophagy-related genes by different miRNAs in various pathological conditions, including cancer, kidney and liver disorders, neurodegeneration, cardiovascular disorders, infectious diseases, aging-related conditions, and inflammation-related diseases. As miRNAs are being identified as prime regulators of autophagy in human disease, pharmacological molecules and traditional medicines targeting these miRNAs are also being tested in disease models, thus initiating a new series of therapeutic interventions targeting autophagy.

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Autophagy is activated in human spermatozoa subjected to oxidative stress and its inhibition impairs sperm quality and promotes cell death

et al. 2022

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STUDY QUESTION Does oxidative stress (OS) activate autophagy in human sperm? SUMMARY ANSWER Human spermatozoa subjected to OS activate an autophagic response. WHAT IS KNOWN ALREADY Autophagy is a regulated pathway of lysosomal degradation which helps eukaryotic cells to maintain or restore homeostasis, being a cellular stress response mechanism. OS is a main cause of impaired sperm function and is linked to male infertility; however, whether OS activates autophagy in human spermatozoa is unknown. STUDY DESIGN, SIZE, DURATION Human spermatozoa were exposed separately to ionomycin and hydrogen peroxide in order to induce OS. An untreated control group was included. Sperm cells under OS were then exposed to chloroquine in order to block autophagy. An untreated control and a control incubated only with the OS inducer were included in each experimental setting. PARTICIPANTS/MATERIALS, SETTING, METHODS For this study, semen samples from normozoospermic donors were used and motile sperm cells were selected by the swim up technique. First, the generation of OS under our experimental conditions was demonstrated by analyzing sperm parameters including viability, reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm) motility and thiol oxidation. Then, proteins involved in autophagy, including the microtubule-associated protein light chain 3 (LC3), particularly LC3-I and LC3-II, autophagy-related 5 (ATG5) and autophagy-related 16 (ATG16) proteins as well as the phosphorylated form of AMP-activated protein kinase (pAMPK) were evaluated in spermatozoa exposed to OS and compared to the untreated control. Finally, the impact of autophagy blocking by chloroquine treatment on sperm quality, metabolic parameters, including glycolysis and oxidative phosphorylation, as well as the cell death markers phosphatidylserine externalization and caspase activation was analyzed. Sperm quality parameters, cell death markers and autophagy-related proteins were analyzed by flow cytometry. Motility was evaluated by the computer-assisted sperm analysis system and metabolic parameters were analyzed using an extracellular flux analyzer. MAIN RESULTS AND THE ROLE OF CHANCE Exposure to ionomycin and hydrogen peroxide promotes OS resulting in increased ROS production and decreased viability, ΔΨm and motility, while increasing thiol oxidation. These alterations were accompanied by a decrease in LC3-I, indicating that autophagy was activated upon OS exposure. Ionomycin also caused an increase in LC3-II, ATG5, ATG16 and pAMPK content. Autophagy blocking of sperm exposed to OS caused deterioration in sperm quality and metabolic parameters as well as an increase in cell death markers. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The study was carried out in vitro using motile sperm from normozoospermic donors; tests on sperm from infertile patients were not carried out. The autophagy blocking plus OS might generate a non-specific response to a highly stressful situation leading to the induction of cell death. WIDER IMPLICATIONS OF THE FINDINGS Human spermatozoa subjected to OS activate an autophagic response and its blockage results in increased oxidative damage and commits spermatozoa to cell death. These results suggest a crucial role of autophagy as a stress response by male gametes, which contributes to maintaining the functionality and lifespan of ejaculated sperm cells. Detection of autophagy activation in sperm cells ex vivo could be included in semen analysis as a marker of OS, especially in men displaying high levels of seminal ROS. Novel strategies that aim to activate this cellular stress response could improve sperm quality/functionality under natural ejaculate conditions in which increased ROS levels are expected. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Fondo Nacional de Investigación Científica y Tecnológica, Chile (ANID/FONDECYT, Grant number 11170758 to P.U.); the Comisión Nacional de Investigación Científica y Tecnológica, Chile (ANID/CONICYT, Grant number PAI79160030 to P.U.) and the Dirección de Investigación, Universidad de La Frontera. The authors disclose no potential conflicts of interest.

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Preface—Autophagy: An old mechanism with new challenges ahead

Cited by 3 publications

References 50 publications

MicroRNAs in Age-Related Proteostasis and Stress Responses

MicroRNAs in Age-Related Proteostasis and Stress Responses

Regulation of autophagy by miRNAs in human diseases

Autophagy is activated in human spermatozoa subjected to oxidative stress and its inhibition impairs sperm quality and promotes cell death

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