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ER tubules mark sites of mitochondrial division.
Science. 2011 Oct 21; 334(6054):358-62
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14 Oct 2011
New Finding
DOI: 10.3410/f.13352964.14724066
This paper describes in a beautiful and elegant study that, where endoplasmic reticulum (ER) tubules wrap around mitochondria, they reduce the diameter of the mitochondria, which subsequently allows the efficient recruitment of the dynamin-like GTPase Dnm1/DRP1 to the site at which mitochondrial fission...Continue reading
This paper describes in a beautiful and elegant study that, where endoplasmic reticulum (ER) tubules wrap around mitochondria, they reduce the diameter of the mitochondria, which subsequently allows the efficient recruitment of the dynamin-like GTPase Dnm1/DRP1 to the site at which mitochondrial fission will occur. Thus, ER-mitochondrial contact is no longer restricted to an exchange of lipids and calcium: the ER appears to play a more active role in the regulation of mitochondrial connectivity and homeostasis.
Disclosures
None declared
Add Comment
Spang A: F1000Prime Recommendation of [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 14 Oct 2011; DOI: 10.3410/f.13352964.14724066. F1000Prime.com/13352964#eval14724066
28 Oct 2011
Hyung Don Ryoo
F1000 Developmental Biology
New York University School of Medicine,
New York, NY, USA.
F1000 Developmental Biology
New York University School of Medicine,
New York, NY, USA.
New Finding
DOI: 10.3410/f.13352964.14726568
The mitochondria is a dynamic organelle whose division and fusion must be regulated to ensure proper cell division, cell death and to prevent various diseases {1}. At the same time, mitochondria makes extensive contacts with the endoplasmic reticulum (ER), which is thought to be important for lipid...Continue reading
The mitochondria is a dynamic organelle whose division and fusion must be regulated to ensure proper cell division, cell death and to prevent various diseases {1}. At the same time, mitochondria makes extensive contacts with the endoplasmic reticulum (ER), which is thought to be important for lipid synthesis and calcium signaling {2}. Here, the authors show that there is another function for the ER-mitochondria interaction -- to mark future mitochondrial fission sites.
Using a combination of high resolution electron microscopy (EM) tomography and fluorescence microscopy, the authors show that the ER wraps around the mitochondria prior to mitochondrial fission. Dynamin-related proteins known to regulate mitochondrial fission localize to this site. Knockdown of known fission regulators does not affect the ER-mitochondria contact at the constriction sites. These observations lead the authors to propose that the ER wraps around the mitochondrial fission sites to constrict them and, subsequently, dynamin-related proteins are recruited to complete the fission process.
Previous work has largely focused on dynamin-related proteins, and their genetic and physical interactors, as regulators of mitochondrial fission. Here, the authors point out that the mitochondrial diameter is normally too big for these proteins to mediate fission directly, and suggest that, prior to this step, the mitochondria needs to be constricted by the ER. What kind of mechanisms are involved in this constriction step remains unknown, and will likely be a topic of future research.
Using a combination of high resolution electron microscopy (EM) tomography and fluorescence microscopy, the authors show that the ER wraps around the mitochondria prior to mitochondrial fission. Dynamin-related proteins known to regulate mitochondrial fission localize to this site. Knockdown of known fission regulators does not affect the ER-mitochondria contact at the constriction sites. These observations lead the authors to propose that the ER wraps around the mitochondrial fission sites to constrict them and, subsequently, dynamin-related proteins are recruited to complete the fission process.
Previous work has largely focused on dynamin-related proteins, and their genetic and physical interactors, as regulators of mitochondrial fission. Here, the authors point out that the mitochondrial diameter is normally too big for these proteins to mediate fission directly, and suggest that, prior to this step, the mitochondria needs to be constricted by the ER. What kind of mechanisms are involved in this constriction step remains unknown, and will likely be a topic of future research.
References
Disclosures
None declared
Ryoo H: F1000Prime Recommendation of [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 28 Oct 2011; DOI: 10.3410/f.13352964.14726568. F1000Prime.com/13352964#eval14726568
28 Oct 2011
New Finding
DOI: 10.3410/f.13352964.14726625
This ground-breaking study uses high-resolution electron microscope (EM) tomography and live-cell imaging approaches to document a tight correlation between formation of tubular endoplasmic reticulum (ER)-mitochondrion contact sites with mitochondrial membrane constriction and recruitment of Drp1 to these...Continue reading
This ground-breaking study uses high-resolution electron microscope (EM) tomography and live-cell imaging approaches to document a tight correlation between formation of tubular endoplasmic reticulum (ER)-mitochondrion contact sites with mitochondrial membrane constriction and recruitment of Drp1 to these mitochondrial fission sites.
Physical interactions between the ER and mitochondria have been appreciated for several years now, but this study provides the first evidence implicating tubular ER elements in direct regulation of mitochondrial morphology.
Physical interactions between the ER and mitochondria have been appreciated for several years now, but this study provides the first evidence implicating tubular ER elements in direct regulation of mitochondrial morphology.
Disclosures
None declared
Barlowe C: F1000Prime Recommendation of [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 28 Oct 2011; DOI: 10.3410/f.13352964.14726625. F1000Prime.com/13352964#eval14726625
04 Nov 2011
New Finding
DOI: 10.3410/f.13352964.14726737
This study provides a morphological description of a new type of inter-organelle contact site between the endoplasmic reticulum (ER) and mitochondria. Membrane contact sites are gaining increasing attention as platforms for inter-organelle communication. With known roles in processes such as lipid and...Continue reading
This study provides a morphological description of a new type of inter-organelle contact site between the endoplasmic reticulum (ER) and mitochondria. Membrane contact sites are gaining increasing attention as platforms for inter-organelle communication. With known roles in processes such as lipid and Ca2+ trafficking, it appears that this largely unexplored area will likely provide fundamental new cell biological insights into intracellular events.
The work of Voeltz and colleagues describes sites of contact between the ER and the mitochondria, where an ER tubule appears to extend perpendicular to the mitochondrial lumen and encapsulates the tubule in an incomplete ring, resembling a clamp. Analysis of the images reveals that the contact is associated with a narrowing of the mitochondrial tubule. The authors suggest that the constriction provides a means of facilitating fusion by changing the diameter of the mitochondrial tubule to a size that is compatible with Drp1/Dmn1 assembly. In both Saccharomyces cerevisiae and COS-7 cells, the presence of the mitochondrial fusion machinery highly correlates with the ER clamp contact. The machinery that mediates this contact, its assembly and disassembly, the location of the clamp contacts, the physiological context and medical relevance of the clamp contact, the relationship of the ER clamp contacts to other types of ER contact sites, and if signaling takes place in both directions between organelles are amongst the myriad questions that are posed by this intriguing finding.
The work of Voeltz and colleagues describes sites of contact between the ER and the mitochondria, where an ER tubule appears to extend perpendicular to the mitochondrial lumen and encapsulates the tubule in an incomplete ring, resembling a clamp. Analysis of the images reveals that the contact is associated with a narrowing of the mitochondrial tubule. The authors suggest that the constriction provides a means of facilitating fusion by changing the diameter of the mitochondrial tubule to a size that is compatible with Drp1/Dmn1 assembly. In both Saccharomyces cerevisiae and COS-7 cells, the presence of the mitochondrial fusion machinery highly correlates with the ER clamp contact. The machinery that mediates this contact, its assembly and disassembly, the location of the clamp contacts, the physiological context and medical relevance of the clamp contact, the relationship of the ER clamp contacts to other types of ER contact sites, and if signaling takes place in both directions between organelles are amongst the myriad questions that are posed by this intriguing finding.
Disclosures
None declared
Collins R: F1000Prime Recommendation of [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 04 Nov 2011; DOI: 10.3410/f.13352964.14726737. F1000Prime.com/13352964#eval14726737
07 Nov 2011
New Finding
DOI: 10.3410/f.13352964.14730078
This fascinating study uses high resolution and live cell imaging to define a novel interaction between the endoplasmic reticulum (ER) and mitochondria.
The interaction occurs on ER tubules devoid of ribosomes, which encircle mitochondria and recruit dynamin-related proteins to mediate mitochondrial...Continue reading
The interaction occurs on ER tubules devoid of ribosomes, which encircle mitochondria and recruit dynamin-related proteins to mediate mitochondrial...Continue reading
This fascinating study uses high resolution and live cell imaging to define a novel interaction between the endoplasmic reticulum (ER) and mitochondria.
The interaction occurs on ER tubules devoid of ribosomes, which encircle mitochondria and recruit dynamin-related proteins to mediate mitochondrial fission. Data are shown from both yeast and mammalian cells. The images are beautiful and nicely illustrate the power of this approach.
The interaction occurs on ER tubules devoid of ribosomes, which encircle mitochondria and recruit dynamin-related proteins to mediate mitochondrial fission. Data are shown from both yeast and mammalian cells. The images are beautiful and nicely illustrate the power of this approach.
Disclosures
None declared
Bogan J: F1000Prime Recommendation of [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 07 Nov 2011; DOI: 10.3410/f.13352964.14730078. F1000Prime.com/13352964#eval14730078
08 Dec 2011
New Finding
DOI: 10.3410/f.13352964.14755062
Mitochondria are very dynamic organelles that are constantly dividing and fusing, and this process has been shown to be essential in maintaining healthy mitochondria. Defects in the processes can lead to several types of mitochondrial disease. This paper presents new data supporting a role for the endoplasmic...Continue reading
Mitochondria are very dynamic organelles that are constantly dividing and fusing, and this process has been shown to be essential in maintaining healthy mitochondria. Defects in the processes can lead to several types of mitochondrial disease. This paper presents new data supporting a role for the endoplasmic reticulum (ER) in mitochondrial fission.
Several dynamin-related GTPases have been shown to be required for mitochondrial fusion and fission but although the protein responsible for outer membrane fission (Drp1 in mammals and Dnm1 in yeast) has been observed to form helices that contract upon GTP hydrolysis {1}, the diameter of the uncontracted helices is much smaller than the diameter of mitochondria prior to fission. Thus, it's difficult to see how the Dnm1/Drp1 helices could assemble on mitochondria unless they are partially constricted by some other mechanism. Close association between mitochondria and the ER has long been noted, supporting known functional interactions in phospholipid biosynthesis and Ca++ regulation. This paper from Dr. Nunnari's lab (Nunnari was one of the authors of the Mears et al. paper {1}, cited above) presents convincing evidence that contact between mitochondria and ER causes constriction of mitochondria to a diameter approaching that of the previously observed Dnm1 helices. Indeed, electron tomograms of ER/mitochondrion contacts at sites of constriction show that the ER wraps around the mitochondrion, and the extent of constriction correlates well with the extent to which the ER encircles the mitochondrion. Fluorescence microscopy demonstrated that the ER-mediated constrictions co-localized with Dnm1/Drp1 and with Mff, a mammalian mitochondrial outer membrane protein required for Drp1 localization and outer membrane fission. Interestingly, however, ER localized at mitochondrial constriction sites, even in the absence of Drp1 and Mff. Thus, there must be as yet unidentified factors responsible for localization of ER to mitochondrial constriction sites.
It is not certain how ER contact causes constriction of mitochondria but, given the correlation of the extent of constriction with the extent to which the ER encircles mitochondria, it's tempting to hypothesize that ER tubules wrap around mitochondria to physically constrict their size to the point that Drp1/Dnm1 helices can assemble around the sites and further constrict them following GTP hydrolysis, thus leading to mitochondrial fission. This model nicely complements a topological model for inner membrane fission that we proposed to explain the transformation during apoptosis of normal mitochondria to a form with separate vesicular matrix compartments {2}, a phenotype that Merkwirth et al. {3} subsequently associated with loss of long isoforms of OPA1, a dynamin-related protein believed to be responsible for inner membrane fusion and regulation of crista morphology.
Several dynamin-related GTPases have been shown to be required for mitochondrial fusion and fission but although the protein responsible for outer membrane fission (Drp1 in mammals and Dnm1 in yeast) has been observed to form helices that contract upon GTP hydrolysis {1}, the diameter of the uncontracted helices is much smaller than the diameter of mitochondria prior to fission. Thus, it's difficult to see how the Dnm1/Drp1 helices could assemble on mitochondria unless they are partially constricted by some other mechanism. Close association between mitochondria and the ER has long been noted, supporting known functional interactions in phospholipid biosynthesis and Ca++ regulation. This paper from Dr. Nunnari's lab (Nunnari was one of the authors of the Mears et al. paper {1}, cited above) presents convincing evidence that contact between mitochondria and ER causes constriction of mitochondria to a diameter approaching that of the previously observed Dnm1 helices. Indeed, electron tomograms of ER/mitochondrion contacts at sites of constriction show that the ER wraps around the mitochondrion, and the extent of constriction correlates well with the extent to which the ER encircles the mitochondrion. Fluorescence microscopy demonstrated that the ER-mediated constrictions co-localized with Dnm1/Drp1 and with Mff, a mammalian mitochondrial outer membrane protein required for Drp1 localization and outer membrane fission. Interestingly, however, ER localized at mitochondrial constriction sites, even in the absence of Drp1 and Mff. Thus, there must be as yet unidentified factors responsible for localization of ER to mitochondrial constriction sites.
It is not certain how ER contact causes constriction of mitochondria but, given the correlation of the extent of constriction with the extent to which the ER encircles mitochondria, it's tempting to hypothesize that ER tubules wrap around mitochondria to physically constrict their size to the point that Drp1/Dnm1 helices can assemble around the sites and further constrict them following GTP hydrolysis, thus leading to mitochondrial fission. This model nicely complements a topological model for inner membrane fission that we proposed to explain the transformation during apoptosis of normal mitochondria to a form with separate vesicular matrix compartments {2}, a phenotype that Merkwirth et al. {3} subsequently associated with loss of long isoforms of OPA1, a dynamin-related protein believed to be responsible for inner membrane fusion and regulation of crista morphology.
References
1.
Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission.
Nat Struct Mol Biol 2011 Jan; 1(18):20-6
PMID: 21170049
2.
Correlated three-dimensional light and electron microscopy reveals transformation of mitochondria during apoptosis.
Nat Cell Biol 2007 Sep; 9(9):1057-65
PMID: 17721514
3.
Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria.
Genes Dev 2008 Feb 15; 4(22):476-88
PMID: 18281461
Disclosures
None declared
Frey T: F1000Prime Recommendation of [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 08 Dec 2011; DOI: 10.3410/f.13352964.14755062. F1000Prime.com/13352964#eval14755062
19 Dec 2011
New Finding
DOI: 10.3410/f.13352964.14779131
I have really nothing to add to the other evaluations, other than to say that this is a very nice piece of work that has some far-reaching implications for both mitochondrial function and endoplasmic reticulum (ER) dynamics.
Disclosures
None declared
Stephens D: F1000Prime Recommendation of [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 19 Dec 2011; DOI: 10.3410/f.13352964.14779131. F1000Prime.com/13352964#eval14779131
F1000Prime Recommendations, Dissents and Comments for [Friedman JR et al., Science 2011, 334(6054):358-62]. In F1000Prime, 19 May 2013; F1000Prime.com/13352964
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Mitochondrial structure and distribution are regulated by division and fusion events. Mitochondrial division is regulated by Dnm1/Drp1, a dynamin-related protein that forms helices around mitochondria to mediate fission. Little is known about what determines sites of mitochondrial fission within the mitochondrial network. The endoplasmic reticulum (ER) and mitochondria exhibit tightly coupled dynamics and have extensive contacts. We tested whether ER plays a role in mitochondrial division. We found that mitochondrial division occurred at positions where ER tubules contacted mitochondria and mediated constriction before Drp1 recruitment. Thus, ER tubules may play an active role in defining the position of mitochondrial division sites.
PMID: 21885730
