ER-mitochondria contacts as sites of mitophagosome formation

Böckler, Stefan; Westermann, Benedikt

doi:10.4161/auto.28981

Cited by 30 publications

(34 citation statements)

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“…Fusion processes mediated by MFN2 are also crucial for the initiation of mitophagy by favoring PINK/Parkin interaction [124,125]. The genetic ablation of MFN2 in fibroblasts, cardiomyocytes, and neurons induces impairment of mitophagy, accumulation of dysfunctional mitochondria, and cell death [126].…”

Section: Endoplasmic Reticulum-mitochondrial Contact Sites Oxidativementioning

confidence: 99%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca 2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson's disease as a prototypical geroscience condition.Cells 2020, 9, 598 2 of 18 instability, telomere attrition, epigenetic alterations, deregulated nutrient sensing, and stem cell exhaustion [3]. According to the geroscience hypothesis, perturbations in these mechanisms increase the susceptibility to most chronic diseases, functional loss, and eventually, death [4]. Hence, these biologic pillars represent ideal targets for interventions to foster healthy aging [5,6].Mitochondrial dysfunction has attracted considerable interest as a target for geroprotective interventions. Indeed, mitochondria play sensor-transducer-effector roles in a multitude of biological processes, including integration of cell death signaling and preservation of cell stemness [7,8]. Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules [9,10]. In particular, mitochondria establish connections with the endosomal compartment [11,12] and lysosomes [13,14]. These interactions support cytosolic shuttle systems of ions and metabolites across organelles [10,15], and participate to the regulation of cellular housekeeping processes [13,14].The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogene...

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Section: Endoplasmic Reticulum-mitochondrial Contact Sites Oxidativementioning

confidence: 99%

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Picca

Calvani

Coelho-Júnior

et al. 2020

Cells

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“…Orthologs of ERMES components have not yet been identified in mammalian cells, but it is likely that MAM proteins serve analogous purposes. Furthermore, MAMs are involved in the process of mitophagy, as ER-mitochondrial contacts are sites of phagophore membrane formation (Bockler and Westermann, 2014a; Bockler and Westermann, 2014b). …”

Section: Physiological Mitochondria-er Interactionsmentioning

confidence: 99%

Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis

Manfredi

Kawamata

2016

Neurobiology of Disease

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Physical and functional interactions between mitochondria and the endoplasmic reticulum (ER) are crucial for cell life. These two organelles are intimately connected and collaborate to essential processes, such as calcium homeostasis and phospholipid biosynthesis. The connections between mitochondria and endoplasmic reticulum occur through structures named mitochondria associated membranes (MAMs), which contain lipid rafts and a large number of proteins, many of which serve multiple functions at different cellular sites. Growing evidence strongly suggest that alterations of ER-mitochondria interactions are involved in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a devastating and rapidly fatal motor neuron disease. Mutations in proteins that participate in ER-mitochondria interactions and MAM functions are increasingly being associated with genetic forms of ALS and other neurodegenerative diseases. This evidence strongly suggests that, rather than considering the two organelles separately, a better understanding of the disease process can derive from studying the alterations in the their crosstalk. In this review we discuss normal and pathological ER-mitochondria interactions and the evidence that link them to ALS.

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“…The organelles which have been implicated as possible membrane sources for a growing phagophore are the ER, [15][16][17][18] Golgi complex, 19,20 plasma membrane, [21][22][23] mitochondria, [24][25][26] and recycling endosomes. 27,28 More recently, novel data is emerging that shows that phagophore biogenesis occurs at the ER mitochondria contact sites, 29,30 and that several organelles may contribute to their formation including ER exit sites 31 and specific coat protein II (COPII)-coated vesicles budding off the ER exit sites, 32 as well as at the ER-Golgi intermediate compartment. 33 All of these findings show the lack of consensus among researchers on the membrane source for the growing phagophore or it may be that all these membranes are somehow involved.…”

Section: Introductionmentioning

confidence: 99%

Ultrastructural relationship of the phagophore with surrounding organelles

et al. 2015

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Abbreviations: 3D, 3 dimensional; ATG, autophagy-related; BSA, bovine serum albumin; COPII, coat protein II; ER, endoplasmic reticulum; ET, electron tomography; GOLGA2/GM130, golgin A2; immunoEM, immuno electron microscopy; LAMP1, lysosomalassociated membrane protein 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MCS, membrane contact site; PBS, phosphate-buffered saline; SB-EM, serial block-face scanning electron microscopy; SEC31A, SEC31 homolog A (S. cerevisiae); TFRC, transferrin receptor; WIPI2, WD repeat domain, phosphoinositide interacting 2.Phagophore nucleates from a subdomain of the endoplasmic reticulum (ER) termed the omegasome and also makes contact with other organelles such as mitochondria, Golgi complex, plasma membrane and recycling endosomes during its formation. We have used serial block face scanning electron microscopy (SB-EM) and electron tomography (ET) to image phagophore biogenesis in 3 dimensions and to determine the relationship between the phagophore and surrounding organelles at high resolution. ET was performed to confirm whether membrane contact sites (MCSs) are evident between the phagophore and those surrounding organelles. In addition to the known contacts with the ER, we identified MCSs between the phagophore and membranes from putative ER exit sites, late endosomes or lysosomes, the Golgi complex and mitochondria. We also show that one phagophore can have simultaneous MCSs with more than one organelle. Future membrane flux experiments are needed to determine whether membrane contacts also signify lipid translocation.

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ER-mitochondria contacts as sites of mitophagosome formation

Cited by 30 publications

References 0 publications

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Mitochondria and endoplasmic reticulum crosstalk in amyotrophic lateral sclerosis

Ultrastructural relationship of the phagophore with surrounding organelles

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