Mitochondria and Melanosomes Establish Physical Contacts Modulated by Mfn2 and Involved in Organelle Biogenesis

Daniele, Tiziana; Hurbain, Ilse; Vago, Riccardo; Casari, Giorgio; Raposo, Graça; Tacchetti, Carlo; Schiaffino, Maria Vittoria

doi:10.1016/j.cub.2014.01.007

Cited by 127 publications

(117 citation statements)

References 43 publications

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“…Furthermore, Mfn2 deletion impacts other facets of ER-mitochondria communication, like phosphatidylcholine (6) and cholesterol (17,18) transfer to the mitochondria. Finally, Mfn2 was found to be specifically enriched by immunoelectron microscopy at the interface between mitochondria and the ER, as well as other organelles heterotypically tethered to the mitochondria, like melanosomes and lipid droplets (19,20). Structurally, homo-or heterotypic in trans interaction between the ER-Mfn2 and mitochondrial Mfn2 or Mfn1 are supported by Mfn2's role in mitochondrial tethering and fusion (21).…”

mentioning

confidence: 87%

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.

415

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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mentioning

confidence: 87%

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.

415

393

View full text Add to dashboard Cite

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“…Furthermore, SIRT1 overexpression reversed pathological events through its interaction with and subsequent deacetylation of MFN2. This mitochondrial outer membrane protein has diverse functions such as mitochondrial fusion (Chen et al., 2003), tethering between mitochondria and endoplasmic reticulum (ER) (de Brito & Scorrano, 2008; Naon et al., 2016), metabolic regulation (Bach et al., 2003; Sebastián et al., 2012), and the endocytic/secretory pathway (Daniele et al., 2014; Zhao et al., 2012). It is currently unknown how SIRT1 and MFN2 are affected by I/R in old hepatocytes.…”

Section: Introductionmentioning

confidence: 99%

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

et al. 2018

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SummaryIschemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age‐mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23–26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near‐complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co‐overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C‐terminus of MFN2, leading to autophagy activation. The SIRT1‐MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

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“…vCLAMP was also shown to be regulated by phosphorylation of Vps39, which might serve as a metabolic switch translating the metabolic state of the cell to changes in contact site size [28]. Interestingly, physical contacts between mitochondria and melanosomes, pigmentsynthesizing lysosome-like organelles, were discovered in mouse, and were correlated with melanosome biogenesis and maturation [58]. In addition, mitochondria-lysosome communication has been shown to be essential for iron transfer in reticulocytes [59].…”

Section: Machinery and Functionmentioning

confidence: 96%

Mitochatting – If only we could be a fly on the cell wall

Eisenberg-Bord

Schuldiner

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Mitochondria, cellular metabolic hubs, perform many essential processes and are required for the production of metabolites such as ATP, iron-sulfur clusters, heme, amino acids and nucleotides. To fulfill their multiple roles, mitochondria must communicate with all other organelles to exchange small molecules, ions and lipids. Since mitochondria are largely excluded from vesicular trafficking routes, they heavily rely on membrane contact sites. Contact sites are areas of close proximity between organelles that allow efficient transfer of molecules, saving the need for slow and untargeted diffusion through the cytosol. More globally, multiple metabolic pathways require coordination between mitochondria and additional organelles and mitochondrial activity affects all other cellular entities and vice versa. Therefore, uncovering the different means of mitochondrial communication will allow us a better understanding of mitochondria and may illuminate disease processes that occur in the absence of proper cross-talk. In this review we focus on how mitochondria interact with all other organelles and emphasize how this communication is essential for mitochondrial and cellular homeostasis. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.

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Mitochondria and Melanosomes Establish Physical Contacts Modulated by Mfn2 and Involved in Organelle Biogenesis

Abstract: Altogether, our findings reveal the presence of an unprecedented physical and functional connection between mitochondria and the secretory/endocytic pathway that goes beyond the ER-mitochondria linkage and is spatially and timely associated to secretory organelle biogenesis.

Cited by 127 publications

References 43 publications

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

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

Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

Mitochatting – If only we could be a fly on the cell wall

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