Diverse Cellular Roles of Autophagy

Morishita, Hideaki; Mizushima, Noboru

doi:10.1146/annurev-cellbio-100818-125300

Cited by 291 publications

(273 citation statements)

References 180 publications

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“…Autophagy is an intracellular degradation process that delivers cytoplasmic materials to lysosomes . It is an essential process that maintains cellular and tissue homeostasis.…”

mentioning

confidence: 99%

Receptor‐Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells

et al. 2020

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Autophagy is an intracellular process that regulates the degradation of cytosolic proteins and organelles. Dying cells often accumulate autophagosomes. However, the mechanisms by which necroptotic stimulation induces autophagosomes are not defined. Here, we demonstrate that the activation of necroptosis with TNF-a plus the cell-permeable pan-caspase inhibitor Z-VAD induces LC3-II and LC3 puncta, markers of autophagosomes, via the receptor-interacting protein kinase 3 (RIPK3) in intestinal epithelial cells. Surprisingly, necroptotic stimulation reduces autophagic activity, as evidenced by enlarged puncta of the autophagic substrate SQSTM1/p62 and its increased colocalization with LC3. However, necroptotic stimulation does not induce the lysosomal-associated membrane protein 1 (LAMP1) nor syntaxin 17, which mediates autophagosome-lysosome fusion, to colocalize with LC3. These data indicate that necroptosis attenuates autophagic flux before the lysosome fusion step. Our findings may provide insights into human diseases involving necroptosis.

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“…Autophagy is an intracellular degradation process that delivers cytoplasmic materials to lysosomes . It is an essential process that maintains cellular and tissue homeostasis.…”

mentioning

confidence: 99%

Receptor‐Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells

et al. 2020

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“…Significantly increased Bdnf expression in the TSA-treated cones sorted from independent samples was confirmed by quantitative PCR (qRT-PCR) ( Figure 5C). Moreover, the pathway analysis showed significant upregulation of most of the genes (9/14) related to autophagy (mmu04140), an additional pro-survival mechanism in neurodegenerative diseases ( Figure 5B) (42,43). Upregulation of the autophagy-related-5 gene (Atg5) in surviving cones was confirmed by qRT-PCR ( Figure 5C).…”

Section: Hdac Inhibition Induces Global Changes In Gene-transcriptionmentioning

confidence: 78%

“…Besides increased oxidative stress and inflammation, cone starvation has recently been recognized as one of the main contributors to secondary cone death in RP (3,9,14). Autophagy is the main cellular mechanism for self-nourishment and recycling of metabolites to supplement macromolecules and energy under severe starvation (42,43). The beneficial role of autophagy is demonstrated for the clearance of misfolded proteins in mutation-affected photoreceptors or in dysfunctional RPE in age-related macular degeneration (AMD) (70)(71)(72)(73).…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Samardzija

Corna

Gómez‐Sintes

et al. 2019

Preprint

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Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors while cones remain initially unaffected. Cone death follows rod death secondarily due to increased oxidative stress, inflammation, and loss of structural and nutritional support provided by rods. Here, we show that secondary cone cell death in animal models for RP was associated with an increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at a late stage of the disease, when majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival. Moreover, the surviving cones remained light sensitive and initiated light-driven ganglion cell responses. RNA-seq analysis of protected cones demonstrated that HDAC inhibition led to multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique possibility for a targeted pharmacological protection of both primary degenerating rods and secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients independent of the disease stage.

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“…The relationship between oxidative stress and auto/mitophagy has been studied intensively mostly with the conclusion that oxidative stress, mediated by ROS, activates auto/mitophagy [13, 14]. Given that auto/mitophagy are cell protective systems acquired by eukaryotes during evolution [8, 15], findings about ROS activating auto/mitophagy is rational. The cells need to adapt to acute stress by reinforcing auto/mitophagy.…”

Section: Introductionmentioning

confidence: 99%

Microtubule Defect Involved in ‘Mitophagy Resistance’ Under Subacute Oxidative Stress - Potential Mechanism for Cellular Inflammation

Tamura

Yasuda

Shakuo

et al. 2020

Preprint

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38 [Abstract]39 Introduction: Oxidative stress is considered an essential mechanism in 40 ICU-acquired weakness. The roles of oxidative stress in autophagy/mitophagy 41 dysfunction remains elusive. Microtubule serves as an essential guide rail for 42 auto/mitophagosome trafficking required for proper maturation of 43 auto/mitophagosomes in normal circumstances, and microtubules network 44 formation is regulated by signal transduction mechanisms involving Akt, GSK3β, 45 and the microtubule plus-end tracking molecule, EB1. We have investigated (1) 46 whether oxidative stress affects this pathway, leading to the defective mitophagy 47 response, and (2) whether trehalose, an auto/mitophagy modulator, can 48 ameliorate these pathological conditions. 49 Methods: By stably transfecting markers for auto/mitophagy or MT synthesis, 50 we have established a few new C2C12 myocyte cell lines, expressing, GFP-LC3, 51 EB1-GFP, and/or tandem-fluorescence LC3 (tfLC3). To monitor microtubule 52 network, the cells were stained by SiR-tubulin. The cells were cultured in the 53 presence or absence of oxidative stress by hydrogen peroxide (H2O2) and 54 treated with or without trehalose. The response of mitophagy parameters 55 including vesicle motion and the maturation status was monitored by stimulating 5 56 the cells with carbonyl cyanide m-chlorophenyl hydrazone (CCCP), an 57 established mitophagy inducer, under a time-lapse confocal microscopy. Signal 58 transduction mechanisms linking mitophagy to microtubule formation was 59 analyzed by Western Blotting against Akt and GSK3β.60 Results: Cells under the oxidative stress, showed abolished MT network 61 formation, decreased microtubule synthesis by EB1, and a decrease in 62 CCCP-invoked response of mitophagosome motion, perturbed mitophagosome 63 maturation, and increased superoxide production. Signal resistance of 64 Akt/GSK3β pathway to mitophagic stimulation, was documented. Trehalose 65 treatment reversed signal resistance, diminished MT synthesis, ameliorated the 66 disturbed MT network, and improved maturation defects, suppressing the 67 production of superoxide. 68 Conclusions: Oxidative stress decreases the response of mitophagy and 69 abolishes microtubule network. Trehalose improves the synthetic ability of 70 microtubule and normalized the disturbed microtubule network, resulting in the 71 improvement of the perturbed mitophagosomes maturation under the oxidative 72 stress. 73 6 74 [Keywords] 75 Muscle weakness, ICU-acquired weakness, Autophagy, Mitophagy, Oxidative 76 stress, Microtubule, Akt, GSK3β, Trehalose, Mitochondria 7 77 [Introduction] 78 Muscle wasting and muscle weakness is one of the major complications among 79 many types of critical illnesses including sepsis, burn, and major trauma [1]. In 80 critical illnesses, muscle wasting occurs mostly in chronic phase. More recently, 81 however, ICU-acquired weakness (ICU-AW), which occurs rapidly in the 82 critically ill patients, has acquired both scientific and clinical attention in the field 83 of critical illnes...

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Diverse Cellular Roles of Autophagy

Cited by 291 publications

References 180 publications

Receptor‐Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells

Receptor‐Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Microtubule Defect Involved in ‘Mitophagy Resistance’ Under Subacute Oxidative Stress - Potential Mechanism for Cellular Inflammation

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