MITOL Regulates Endoplasmic Reticulum-Mitochondria Contacts via Mitofusin2

Sugiura, Ayumu; Nagashima, Shun; Tokuyama, Takeshi; Amo, Taku; Matsuki, Yohei; Ishido, Satoshi; Kudo, Yoshihisa; McBride, Heidi M.; Fukuda, Toshifumi; Matsushita, Nobuko; Inatome, Ryoko; Yanagi, Shigeru

doi:10.1016/j.molcel.2013.04.023

Cited by 256 publications

(206 citation statements)

References 35 publications

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“…Consistent with this, Mfn2 ablation in murine fibroblasts disrupted ER-mitochondria contact sites, and led to an increased distance and change in morphology of both ER and mitochondria (de Brito & Scorrano, 2008). Furthermore, a mitochondrial ubiquitin ligase (MITOL), which mediates the addition of non-degrading lysine 63-linked polyubiquitin chains on mitochondrially localized Mfn2, was shown to increase the formation of ER-mitochondria contacts (Sugiura et al, 2013). However, the specific mechanisms by which Mfn2 modulates ER-mitochondria contact sites are yet to be defined (Ishihara et al, 2004;Koshiba et al, 2004;de Brito & Scorrano, 2008).…”

Section: Extra-mitochondrial Role Of Mitofusin-2supporting

confidence: 56%

Structure, function, and regulation of mitofusin‐2 in health and disease

2017

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Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non-neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.

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Section: Extra-mitochondrial Role Of Mitofusin-2supporting

confidence: 56%

Structure, function, and regulation of mitofusin‐2 in health and disease

2017

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“…If Mfn2 ablation decreases ER-mitochondria tethering, crosstalk between the two organelles should be altered, as reported by many (10,13,14,16,28). However, the key feature of reduced mitochondrial Ca 2+ uptake following agonist induced ER Ca 2+ release in Mfn2 −/− MEFs was explained not as a consequence of lower tethering, but of lower MCU levels (26).…”

Section: Mfn2mentioning

confidence: 83%

“…Mfn2-dependent tethering is regulated by posttranslational modifications: nondegradative Mfn2 ubiquitination by the E3 ligase MITOL reduces ER-mitochondria tethering and Ca 2+ transfer without affecting mitochondrial or ER morphology (16). Furthermore, Mfn2 deletion impacts other facets of ER-mitochondria communication, like phosphatidylcholine (6) and cholesterol (17,18) transfer to the mitochondria.…”

mentioning

confidence: 99%

Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum–mitochondria tether

Naón

Zaninello

Giacomello

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

413

393

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The discovery of the multiple roles of mitochondria-endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER-mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2's role in ER-mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER-mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion. Functionally, mitochondrial uptake of Ca 2+ released from the ER was reduced following acute Mfn2 ablation, as well as in Mfn2−/− cells overexpressing the mitochondrial calcium uniporter. Mitochondrial Ca 2+ uptake rate and extent were normal in isolated Mfn2 −/− liver mitochondria, consistent with the finding that acute or chronic Mfn2 ablation or overexpression did not alter mitochondrial calcium uniporter complex component levels. Hence, Mfn2 stands as a bona fide ER-mitochondria tether whose ablation decreases interorganellar juxtaposition and communication.he endoplasmic reticulum (ER) and mitochondria are physically coupled to control mitochondrial Ca 2+ uptake, lipid transfer, autophagosome formation, ER stress, and apoptosis (1-6). Juxtaposition is mediated by protein structures that can be visualized in electron microscopy (EM) and electron tomography (ET) studies. These physical tethers span 6-15 nm when connecting smooth, and 19-30 nm when connecting rough ER to mitochondria (7). Operationally, an ER-mitochondria tether should fulfill at least these minimal criteria: (i) it is retrieved on the outer mitochondrial membrane (OMM); (ii) it is retrieved in mitochondria-associated ER membranes, the ER subdomain involved in interaction with mitochondria; (iii) it interacts in trans with a homo-or heterotypic interactor on the opposing membrane; (iv) its deletion increases the distance between the ER and mitochondria; or (v) its deletion reduces exchange of Ca 2+ and lipids between the ER and mitochondria. The molecular nature of ER-mitochondria tethers remained elusive for many years. The scaffold protein PACS2 (phosphofurin acidic cluster sorting protein 2) modulates their extent (8), and they include the heterotypic association between the inositol triphosphate (IP3) receptor on the ER and the OMM voltagedependent anion channel (9). Another protein that fulfils the operational criteria to be defined as a tether is Mitofusin 2 (Mfn2). This OMM profusion protein is also retrieved in mitochondria-associated ER membranes and ER Mfn2 interacts in trans with Mfn1 or Mfn2 on the mitochondria to physically tether the organelles. Mfn2 ablation increases the distance between the ER and mitochondria and decreases agonist-evoked Ca 2+ transfer from the ER to mitochondria (10) that depends on the generation of high Ca 2+ microdomains at their interface (11,12). The role of Mfn2 as a tether was confirmed independently in the heart (13), in pro-opiomelanocortin neurons (14), and in the liver (15).Mfn2-dependent tethe...

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“…MFN2 is also activated by the mitochondrial ubiquitin ligase MITOL [51]. MITOL-mediated K63-linked MFN2 ubiquitination promotes its GTP-binding activity and leads to MFN2 oligomerization for MAM formation and stabilization.…”

Section: Mitochondrial Fusionmentioning

confidence: 99%