Phagophores evolve from recycling endosomes

Puri, Claudia; Vicinanza, Mariella; Rubinsztein, David C.

doi:10.1080/15548627.2018.1482148

Cited by 24 publications

(14 citation statements)

References 1 publication

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“…We went on to examine endosomal and lysosomal function following long-term hypoxia in cardiomyocytes. Firstly, immunofluorescence was performed to discriminate endosomes and lysosomes using COXIV (green, mitochondria) and RAB5 (red, early endosomes) 45 , RAB11 (red, recycling endosomes) 46 and LAMP1 (red, lysosomes) 47 . Under 9-h hypoxia, enlarged vacuoles (red) were observed and positive with LAMP1, not with RAB5 or RAB11, indicative of enlargement of lysosomes, suggesting that lysosomal dysfunction may be involved in mitophagy flux suppression following long-term hypoxia (Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury

Sun

et al. 2020

Theranostics

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Rationale: Ischemic heart disease remains a primary threat to human health, while its precise etiopathogenesis is still unclear. TBC domain family member 15 (TBC1D15) is a RAB7 GTPase-activating protein participating in the regulation of mitochondrial dynamics. This study was designed to explore the role of TBC1D15 in acute myocardial infarction (MI)-induced cardiac injury and the possible mechanism(s) involved. Methods: Mitochondria-lysosome interaction was evaluated using transmission electron microscopy and live cell time-lapse imaging. Mitophagy flux was measured by fluorescence and western blotting. Adult mice were transfected with adenoviral TBC1D15 through intra-myocardium injection prior to a 3-day MI procedure. Cardiac morphology and function were evaluated at the levels of whole-heart, cardiomyocytes, intracellular organelles and cell signaling transduction. Results: Our results revealed downregulated level of TBC1D15, reduced systolic function, overt infarct area and myocardial interstitial fibrosis, elevated cardiomyocyte apoptosis and mitochondrial damage 3 days after MI. Overexpression of TBC1D15 restored cardiac systolic function, alleviated infarct area and myocardial interstitial fibrosis, reduced cardiomyocyte apoptosis and mitochondrial damage although TBC1D15 itself did not exert any myocardial effect in the absence of MI. Further examination revealed that 3-day MI-induced accumulation of damaged mitochondria was associated with blockade of mitochondrial clearance because of enlarged defective lysosomes and subsequent interrupted mitophagy flux, which were attenuated by TBC1D15 overexpression. Mechanistic studies showed that 3-day MI provoked abnormal mitochondria-lysosome contacts, leading to lysosomal enlargement and subsequently disabled lysosomal clearance of damaged mitochondria. TBC1D15 loosened the abnormal mitochondria-lysosome contacts through both the Fis1 binding and the RAB7 GAPase-activating domain of TBC1D15, as TBC1D15-dependent beneficial responses were reversed by interference with either of these two domains both in vitro and in vivo . Conclusions: Our findings indicated a pivotal role of TBC1D15 in acute MI-induced cardiac anomalies through Fis1/RAB7 regulated mitochondria-lysosome contacts and subsequent lysosome-dependent mitophagy flux activation, which may provide a new target in the clinical treatment of acute MI.

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Section: Resultsmentioning

confidence: 99%

TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury

Sun

et al. 2020

Theranostics

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“…The first autophagic structure to be formed is a cup-shaped double-membrane vesicle, called an isolation membrane or phagophore. According to the analysis of the lipid and protein content, phagophores stem from endoplasmic reticulum, but, for their expansion, receive further contributions from multiple sources, including recycling endosomes, mitochondria, Golgi and lipid droplets [ 102 , 103 , 104 , 105 , 106 , 107 ]. The entire process of nucleation, expansion, closure and, eventually, fusion with lysosomes is made possible by the recruitment of a wide array of proteins from cytosol.…”

Section: Autophagic Structures and Associated Protein Markersmentioning

confidence: 99%

Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

Thellung

Corsaro

Nizzari

et al. 2019

IJMS

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The aim of this review is to critically analyze promises and limitations of pharmacological inducers of autophagy against protein misfolding-associated neurodegeneration. Effective therapies against neurodegenerative disorders can be developed by regulating the “self-defense” equipment of neurons, such as autophagy. Through the degradation and recycling of the intracellular content, autophagy promotes neuron survival in conditions of trophic factor deprivation, oxidative stress, mitochondrial and lysosomal damage, or accumulation of misfolded proteins. Autophagy involves the activation of self-digestive pathways, which is different for dynamics (macro, micro and chaperone-mediated autophagy), or degraded material (mitophagy, lysophagy, aggrephagy). All neurodegenerative disorders share common pathogenic mechanisms, including the impairment of autophagic flux, which causes the inability to remove the neurotoxic oligomers of misfolded proteins. Pharmacological activation of autophagy is typically achieved by blocking the kinase activity of mammalian target of rapamycin (mTOR) enzymatic complex 1 (mTORC1), removing its autophagy suppressor activity observed under physiological conditions; acting in this way, rapamycin provided the first proof of principle that pharmacological autophagy enhancement can induce neuroprotection through the facilitation of oligomers’ clearance. The demand for effective disease-modifying strategies against neurodegenerative disorders is currently stimulating the development of a wide number of novel molecules, as well as the re-evaluation of old drugs for their pro-autophagic potential.

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“…The final stage of phagophore differentiation is the complete surrounding of the cargo and its sequestration inside the autophagosome. This is a vesicle with a double, bilayer lipid-protein membrane, containing cargo intended for autophagic degradation [24][25][26][27][28][29]. The mechanisms of these initial stages have been intensively studied and described in numerous review papers, e.g., [30][31][32][33].…”

Section: Formation and Trafficking Of Autophagosomementioning

confidence: 99%

Completing Autophagy: Formation and Degradation of the Autophagic Body and Metabolite Salvage in Plants

Stefaniak

Wojtyla

Pietrowska‐Borek

et al. 2020

IJMS

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Autophagy is an evolutionarily conserved process that occurs in yeast, plants, and animals. Despite many years of research, some aspects of autophagy are still not fully explained. This mostly concerns the final stages of autophagy, which have not received as much interest from the scientific community as the initial stages of this process. The final stages of autophagy that we take into consideration in this review include the formation and degradation of the autophagic bodies as well as the efflux of metabolites from the vacuole to the cytoplasm. The autophagic bodies are formed through the fusion of an autophagosome and vacuole during macroautophagy and by vacuolar membrane invagination or protrusion during microautophagy. Then they are rapidly degraded by vacuolar lytic enzymes, and products of the degradation are reused. In this paper, we summarize the available information on the trafficking of the autophagosome towards the vacuole, the fusion of the autophagosome with the vacuole, the formation and decomposition of autophagic bodies inside the vacuole, and the efflux of metabolites to the cytoplasm. Special attention is given to the formation and degradation of autophagic bodies and metabolite salvage in plant cells.

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Phagophores evolve from recycling endosomes

Cited by 24 publications

References 1 publication

TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury

TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury

Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

Completing Autophagy: Formation and Degradation of the Autophagic Body and Metabolite Salvage in Plants

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