Drp1 Tubulates the ER in a GTPase-Independent Manner

Adachi, Yoshihiro; Kato, Takashi; Yamada, Tatsuya; Murata, Daisuke; Arai, Kenta; Stahelin, Robert V.; Chan, David C.; Iijima, Miho; Sesaki, Hiromi

doi:10.1016/j.molcel.2020.10.013

Cited by 41 publications

(58 citation statements)

References 52 publications

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“…This allows the ER protein inverted formin 2 (INF2) and the mitochondrial protein actin-nucleating Spire and Arp2/3 complexes to recruit actin–myosin assembles, which, together with Drp1, induce mitochondrial fission [ 128 , 129 , 130 , 131 ]. More recently, a study showed that Drp1 is associated with the ER during the mitochondrial fission process, tubulating the ER and facilitating its interaction with mitochondria [ 132 ]. Moreover, this process seems to be regulated by mechanisms in the mitochondrial matrix, since actively replicating mtDNA is present in these ER-associated mitochondrial constriction and division sites, suggesting coordination between mtDNA synthesis and mitochondrial division [ 133 , 134 ].…”

Section: Mitochondria–er Contact Sites and Mitochondria-associatedmentioning

confidence: 99%

Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases

Leal

Martins

2021

Biomedicines

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The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria–ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer’s disease as well as Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer’s disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration.

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Section: Mitochondria–er Contact Sites and Mitochondria-associatedmentioning

confidence: 99%

Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases

Leal

Martins

2021

Biomedicines

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“…Following ER tubule encirclement of the mitochondria, it has been proposed that INF2-induced actin polymerization occurs, triggering an initial constriction mechanism to facilitate DRP1 recruitment, assembly and final scission of the membrane ( Korobova et al, 2013 ; Pon, 2013 ). A subset of DRP1 is responsible for tubulating the ER, independent of its GTPase or oligomerization activities, and is mediated by the less-well characterized variable domain, indicating DRP1 may have fission-independent functions that have yet to be established ( Adachi et al, 2020 ). In addition to these mechanisms, Golgi-derived vesicles driven by the activity of the small guanosine triphosphatase ADP-ribosylation factor 1 (Arf1) and or its effector PI(4)KIIIβ are required for complete fission of the mitochondria ( Nagashima et al, 2020 ).…”

Section: Mitochondrial Dynamicsmentioning

confidence: 99%

Dynamic properties of mitochondria during human corticogenesis

Baum

Gama

2021

Development

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Mitochondria are signaling hubs responsible for the generation of energy through oxidative phosphorylation, the production of key metabolites that serve the bioenergetic and biosynthetic needs of the cell, calcium (Ca2+) buffering and the initiation/execution of apoptosis. The ability of mitochondria to coordinate this myriad of functions is achieved through the exquisite regulation of fundamental dynamic properties, including remodeling of the mitochondrial network via fission and fusion, motility and mitophagy. In this Review, we summarize the current understanding of the mechanisms by which these dynamic properties of the mitochondria support mitochondrial function, review their impact on human cortical development and highlight areas in need of further research.

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“…Dynamin-related protein 1 (Drp1) has a crucial role in the mitochondrial fission machinery. Cytosolic Drp1 is recruited to the outer mitochondrial membrane and oligomerizes to activate GTP-dependent mitochondrial fission 16,17 . A Drp1 deficiency impedes mitochondrial fission and induces mitochondrial aggregates, which disturb proper neural development, neuronal fate commitment, neurite extension, dendrite development, and synapse formation 18,19 .…”

Section: Introductionmentioning

confidence: 99%

“…SUMOylation contributes to Drp1 stability, whereas deSUMOylation decreases it [21][22][23] . Further, Drp1 localizes to the lumen of the endoplasmic reticulum (ER) 17 , and ER-associated Drp1 induces ER tubulation. ER tubules mechanically contact the mitochondria, which facilitates the recruitment of cytosolic Drp1 to the contact sites.…”

Section: Introductionmentioning

confidence: 99%

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Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development

Yamada

Sato

Akiyama

et al. 2021

Preprint

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Brain development is a highly orchestrated process requiring spatiotemporally regulated mitochondrial dynamics. Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1. We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects Drp1 ubiquitination and tubulation of the endoplasmic reticulum (ER), thereby influencing mitochondrial morphology. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post translational modification, in which a deSUMOylation enzyme isoform competitively regulates mitochondrial dynamics and ER tubulation via Drp1 SUMOylation levels in a tightly controlled process of neuronal differentiation and corticogenesis.

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Drp1 Tubulates the ER in a GTPase-Independent Manner

Cited by 41 publications

References 52 publications

Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases

Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases

Dynamic properties of mitochondria during human corticogenesis

Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development

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