Mitofusin-2 Independent Juxtaposition of Endoplasmic Reticulum and Mitochondria: An Ultrastructural Study

Cosson, Pierre; Marchetti, Anna; Ravazzola, Mariella; Orci, Lelio

doi:10.1371/journal.pone.0046293

Cited by 206 publications

(192 citation statements)

References 23 publications

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“…Mfn2 has been proposed to influence the interaction between mitochondria and other organelles, such as the endoplasmic reticulum (ER) (de Brito & Scorrano, 2008; Cosson et al , 2012; Filadi et al , 2015). In line with this, Mfn2 deficiency has been shown to trigger ER stress at least in liver, brain, and muscle (Sebastian et al , 2012; Schneeberger et al , 2013).…”

Section: Resultsmentioning

confidence: 99%

“…Many of these effects have been attributed to the ability of Mfn2 to mediate not only mitochondria–mitochondria contacts, but also to influence the interaction of mitochondria with other cellular membrane organelles. For example, Mfn2 has a critical role in the maintenance of mitochondria–endoplasmic reticulum (ER) interactions (de Brito & Scorrano, 2008; Cosson et al , 2012; Filadi et al , 2015), and ablation of Mfn2 triggered ER stress in virtually all models tested (Sebastian et al , 2012; Schneeberger et al , 2013). …”

Section: Introductionmentioning

confidence: 99%

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Mfn2 is critical for brown adipose tissue thermogenic function

et al. 2017

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Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine‐tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin‐resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose‐specific Mfn2 knockout (Mfn2‐adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2‐adKO mice were protected from high‐fat diet‐induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole‐body energy homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mfn2 is critical for brown adipose tissue thermogenic function

et al. 2017

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“…To test this hypothesis, we visualized ER-mitochondria contacts by conventional EM (Fig. 6A) and quantified their frequency in WT and in mNEET KO cells, as previously described (17). The perimeter of mitochondrial sections was measured, as well as the zones engaged into close contact with the ER (Table S4).…”

Section: Resultsmentioning

confidence: 99%

MitoNEET-dependent formation of intermitochondrial junctions

Vernay

Marchetti

Sabra

et al. 2017

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

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MitoNEET (mNEET) is a dimeric mitochondrial outer membrane protein implicated in many facets of human pathophysiology, notably diabetes and cancer, but its molecular function remains poorly characterized. In this study, we generated and analyzed mNEET KO cells and found that in these cells the mitochondrial network was disturbed. Analysis of 3D-EM reconstructions and of thin sections revealed that genetic inactivation of mNEET did not affect the size of mitochondria but that the frequency of intermitochondrial junctions was reduced. Loss of mNEET decreased cellular respiration, because of a reduction in the total cellular mitochondrial volume, suggesting that intermitochondrial contacts stabilize individual mitochondria. Reexpression of mNEET in mNEET KO cells restored the WT morphology of the mitochondrial network, and reexpression of a mutant mNEET resistant to oxidative stress increased in addition the resistance of the mitochondrial network to H 2 O 2 -induced fragmentation. Finally, overexpression of mNEET increased strongly intermitochondrial contacts and resulted in the clustering of mitochondria. Our results suggest that mNEET plays a specific role in the formation of intermitochondrial junctions and thus participates in the adaptation of cells to physiological changes and to the control of mitochondrial homeostasis.mitoNEET | CISD1 | mitochondria | intermitochondrial junctions | endoplasmic reticulum

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“…Interestingly, PACS2 interacts with SIRT1 and undergoes SIRT1‐mediated deacetylation (Atkins et al., 2014). Therefore, the severe reduction of MFN2 expression during ischemia can alter the integrity of mitochondria‐ER interaction, thereby disrupting the platform for autophagosome or mitophagosome formation, although some reports do not support this tethering function of MFN2 (Cosson, Marchetti, Ravazzola & Orci, 2012; Filadi et al., 2015, 2017). Alternatively, pathologically low levels of MFN2 may adversely affect the delivery of autophagosomes to lysosomes, as MFN2 may be involved in the fusion between the autophagosome and the lysosome through its interaction with the Ras‐related protein Rab7 (Zhao et al., 2012).…”

Section: Discussionmentioning

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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Mitofusin-2 Independent Juxtaposition of Endoplasmic Reticulum and Mitochondria: An Ultrastructural Study

Cited by 206 publications

References 23 publications

Mfn2 is critical for brown adipose tissue thermogenic function

Mfn2 is critical for brown adipose tissue thermogenic function

MitoNEET-dependent formation of intermitochondrial junctions

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

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