ER platforms mediating autophagosome generation

Ktistakis, Nicholas T.

doi:10.1016/j.bbalip.2019.03.005

Cited by 30 publications

(26 citation statements)

References 76 publications

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“…As discussed earlier, during amino acid starvation autophagosomes form in ER platforms called omegasomes which are marked by the omegasome marker DFCP1 (Axe et al, 2008). Thus, a candidate membrane donor has been proposed to be the ER, with contributions from virtually all intracellular membranes in a way not entirely clear (Ktistakis, 2020). When it comes to mitophagy and other types of selective autophagy our understanding of the membrane source(s), and whether this differs from bulk autophagy, is even less clear.…”

Section: Is There a Membrane Source Specific For Mitophagy?mentioning

confidence: 99%

“…Since observations from other research groups support the notion that mitophagosomes (independently of induction mode) form within omegasomes (Yang and Yang, 2013;Wong and Holzbaur, 2014;Gelmetti et al, 2017;Hsieh and Yang, 2019) it is possible that the ER plays a key role as a membrane source for mitophagy in general. It will be interesting to determine if the different ER proteins that have been reported to be involved in autophagosome biogenesis upon amino acid starvation are also important for mitophagy as well (Walker and Ktistakis, 2019;Ktistakis, 2020). It was recently reported that in yeast mitochondria-ER contact sites are crucial for mitophagy (and pexophagy) to occur (Bockler and Westermann, 2014;Liu et al, 2018).…”

Section: Is There a Membrane Source Specific For Mitophagy?mentioning

confidence: 99%

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Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

Zachari

Ktistakis

2020

Front. Cell Dev. Biol.

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Mitophagy, a conserved intracellular process by which mitochondria are eliminated via the autophagic machinery, is a quality control mechanism which facilitates maintenance of a functional mitochondrial network and cell homeostasis, making it a key process in development and longevity. Mitophagy has been linked to multiple human disorders, especially neurodegenerative diseases where the long-lived neurons are relying on clearance of old/damaged mitochondria to survive. During the past decade, the availability of novel tools to study mitophagy both in vitro and in vivo has significantly advanced our understanding of the molecular mechanisms governing this fundamental process in normal physiology and in various disease models. We here give an overview of the known mitophagy pathways and how they are induced, with a particular emphasis on the early events governing mitophagosome formation.

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Section: Is There a Membrane Source Specific For Mitophagy?mentioning

confidence: 99%

Section: Is There a Membrane Source Specific For Mitophagy?mentioning

confidence: 99%

Mammalian Mitophagosome Formation: A Focus on the Early Signals and Steps

Zachari

Ktistakis

2020

Front. Cell Dev. Biol.

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“…In mammalian cells, PS is synthesized in the ER, transferred through the MERCs to the mitochondria, and transformed into PE (72). A fraction of the mitochondrial-generated PE is then shuttled back to the ER for the generation of isolation membranes, where PE is used for the lipidation of specific adaptor proteins that recruit autophagic cargoes ( Figure 3A) (86,87). In our studies, none of the Miro1-mutant fibroblast lines showed an increase in the amount of newly synthesized autophagosomes following starvation conditions (13,14).…”

Section: Miro1 As a Regulator Of Mitochondrial-er Contact Sitesmentioning

confidence: 99%

The Emerging Role of RHOT1/Miro1 in the Pathogenesis of Parkinson's Disease

et al. 2020

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The expected increase in prevalence of Parkinson's disease (PD) as the most common neurodegenerative movement disorder over the next years underscores the need for a better understanding of the underlying molecular pathogenesis. Here, first insights provided by genetics over the last two decades, such as dysfunction of molecular and organellar quality control, are described. The mechanisms involved relate to impaired intracellular calcium homeostasis and mitochondrial dynamics, which are tightly linked to the cross talk between the endoplasmic reticulum (ER) and mitochondria. A number of proteins related to monogenic forms of PD have been mapped to these pathways, i.e., PINK1, Parkin, LRRK2, and α-synuclein. Recently, Miro1 was identified as an important player, as several studies linked Miro1 to mitochondrial quality control by PINK1/Parkin-mediated mitophagy and mitochondrial transport. Moreover, Miro1 is an important regulator of mitochondria-ER contact sites (MERCs), where it acts as a sensor for cytosolic calcium levels. The involvement of Miro1 in the pathogenesis of PD was recently confirmed by genetic evidence based on the first PD patients with heterozygous mutations in RHOT1/Miro1. Patient-based cellular models from RHOT1/Miro1 mutation carriers showed impaired calcium homeostasis, structural alterations of MERCs, and increased mitochondrial clearance. To account for the emerging role of Miro1, we present a comprehensive overview focusing on the role of this protein in PD-related neurodegeneration and highlighting new developments in our understanding of Miro1, which provide new avenues for neuroprotective therapies for PD patients.

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“…Vesicles carrying the transmembrane protein ATG9 are derived from RAB11-positive recycling endosomes (REs) and the TGN and shuttle rapidly between a starvation-enhanced peripheral reservoir and the PAS, hinting at RE or TGN as sources of lipids (2). Several imaging approaches identified the ER-associated specialized omega-shape domain (omegasome) as the PAS, which is supported by local enrichment and direct functional involvement of ER-resident integral membrane proteins in autophagy from omegasome formation up to autophagosome maturation (3). More recently, REs were named as PASs; however, the link to RE-derived ATG9 vesicles remained unclear (4).…”

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confidence: 98%

“…More recently, REs were named as PASs; however, the link to RE-derived ATG9 vesicles remained unclear (4). In contrast, ATG9 vesicles had been shown to mark a ULK1 landing site on the ER (3). The accurate role of ATG9 is therefore key to understanding autophagy.…”

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confidence: 99%