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    Shape-Changing Mitochondria Are Life Saving Mitochondria
    By Catarina Amorim | April 12th 2011 06:33 AM | 12 comments | Print | E-mail | Track Comments
    About Catarina

    After many years as a scientist (immunology) at Oxford University I moved into scientific journalism and public understanding of science. I am...

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    Mitochondria are better known as the power factories of the cell but in fact they are much more interesting than that. Contrary to the old image in textbooks of round static structures, mitochondria are now known to be incredibly dynamic, shape changing, fusing and dividing according to the multitude of functions they perform in the cell. And now, in a study to be published in the journal Nature Cell Biology, scientists in Italy and Portugal show that mitochondria can also be crucial for the survival of cells during stress. 

    Ligia Gomes, Giulietta Di Benedetto and Luca Scorrano found that when nutrients are scarce, mitochondria “stretch” and fuse creating a tubular network that is much more efficient producing energy allowing cells to continue living even on very little nutrients.

    The discovery of this “survival backup mechanism” is particularly important when we consider the extraordinary number of diseases associated with problems in mitochondria as Gomes – the study’s first author explains – "the discovery of this new behavior can help us in a series of pathologies by finding new strategies to control the survival of the cells whether to avoid them to die excessively as it occurs in neurodegenerative diseases like Alzheimer, or to stop their uncontrolled survival like seen in cancer.” 

    Mitochondria are extraordinary organelles (specialized cellular structures). Semi-autonomous, they have their own DNA as well as the machinery to produce proteins, and are believed to have been once independent organisms that, engulfed by others, eventually lost autonomy (now many of their proteins are produced by the “normal” nucleus DNA). In addition to their key role in the production of energy for all life functions, mitochondria are also important in death, or, more specifically, in apoptosis, a type of cell “suicide” crucial for the body’s normal development - as it gets rid of cells that are old and damaged- and its protection - by eliminating infected or cancerous cells.

    Mitochondrion diagram by Mariana Ruiz Villarreal  These organelles also have an unique dynamic behavior – continuously moving, dividing and fusing – which allows them a variety of functions within the cell.

    For example large interconnected networks of fused mitochondria working together, almost like electric cables, are crucial for metabolism but also to repair damaged mitochondria. Fission (division), on the other hand, is important to create new mitochondria during cell division but also to kill cells. It is this dynamic balance between fusion and fission that allows mitochondria to respond to the energetic demands of the cell but also to an ever-changing environment and it is also in this balance (or lack of it) that scientists believe reside many of the answers to mitochondria-linked diseases. But although the mechanisms behind these “shape-changes” are becoming clear the functions they allow mitochondria to perform are still far from being fully understood.

    Autophagy, for example, is another cellular process that has been linked to mitochondria. Literally meaning “self-devouring” (phagia means devour) autophagy is essential to recycle old, damaged or just unnecessary structures and molecules, as well as eliminate threats like bacteria by “digesting” them inside vesicles. It can also help to cope with stress, for example when nutrients are scarce and the cell is starving, by scavenging non-essential cellular components to recycle for reuse. And while mitochondria can be “devoured” during autophagy there are indications that they can as well participate in the process and this is what Ligia Gomes, Giulietta Di Benedetto and Luca Scorrano from the Dulbecco-Telethon Institute and the Venetian Institute of Molecular Medicine, Padova, Italy and the Center for Neuroscience and Cell Biology, University of Coimbra, Portugal investigate in the study now published.

    Using high resolution microscopy and by marking some mitochondrial proteins with fluorescence Gomes and colleagues were able to track mitochondria during autophagy (induced by starving cells in the laboratory) to see them becoming elongated fusing to form long interconnected networks. Crucially the same was also seen in mice starved for 12 hours proving that this was a real phenomenon. To discover the function of these mitochondrial networks Gomes and colleagues started by identifying the molecules involved in their formation to then block some of them and observe the results.

    They found that when fusion was blocked the cells died much quicker under starvation showing that mitochondria elongation was, somehow, protecting them. Further investigation showed that elongated mitochondria were actually much more effective producing ATP – the energy currency of the cell. In fact, ATP is produced by a protein called ATPase in “factories” located on an internal ridged membrane of the mitochondria. Gomes, Scorrano and colleagues found that elongated mitochondria not only had increased density of ridges (and so more “factories”) but also their ATPase were working in pairs making them much more efficient producing ATP. So elongated mitochondria by being much more efficient using the resources available allowed cells to resist death by starvation for much longer.

    The researchers also look at the cells were mitochondria were incapable of fusing and to their surprise these mitochondria( that lack the capacity to form enough new ATP) start to “cannibalise” the energy of the cells and ultimately kill them. These results show how mitochondria dynamic shape and structure is crucial to what seems an ever-growing number of key roles by mitochondria in the cell. The implications of Gomes and Scorrano’s findings are many. They add to the already impressive list of mitochondrial functions in the cell; from producing energy and inducing cell suicide (apoptosis), we now know that mitochondria can help cell survival in conditions of stress and are part of autophagy. Autophagy and apoptosis are crucial processes to maintain cellular homeostasis, as well as to defend the body against threats as varied as infection and cancer. Mitochondria link to both of them can start explaining the extraordinaire number of diseases associated to dysfunctional mitochondria from Alzheimer’s and Parkinson’s to cancer or even less obvious pathologies such as diabetes and stroke. In fact, defects in mitochondria function are now linked to over 100 diseases and the list continues to grow.

    So to understand better mitochondria as well as the roles and mechanisms of fusion and fission - like Gomes and colleagues’ study did - can ultimately allow scientists and clinicians to manipulate these process targeting mitochondria to improve human health in a multitude of diseases. “This is what is so attractive about fundamental research, which is so many times criticised as a waste of money - says Gomes - because in fact we are studying mechanisms so fundamental for life that discoveries inevitably open new perspectives for health and disease.

    We just need to give them time...”

    Citation: Ligia C. Gomes, Giulietta Di Benedetto&Luca Scorrano, "During autophagy mitochondria elongate, are spared from degradation and sustain cell viability",  Nature Cell Biology, April 10, 2011, doi:10.1038/ncb2220   

    Comments

    Steve Davis
    Thanks Catarina for an excellent article. For those who readers who can actually think, it highlights the contrast between the wonders that can be found in cell studies, and the sterility of the blind alley that is the selfish gene hypothesis. In particular, it brings to the fore the undeniable reality that cooperation is the base feature of life. Descriptions and explanations of the functions of genes and other cell components, fascinating though they may be, are merely descriptions of cooperation in action.
    Gerhard Adam
    Great article! 
    Mundus vult decipi
    amorca
    Thanks guys, Steve I love as you always end up in your pet hate and a simple compliment from you Gerhard the man-that-always-question is very cool .
    Hank
    Neil Shubin can make anything about fish and Steve Davis can make anything about selfish genes.

    Philosophical question, Steve:  'If a tree falls in the forest and no one hears it, is Richard Dawkins still wrong?'

    :)
    Gerhard Adam
    Of course, since Dawkins would've assumed that the tree's genes did it for selfish reasons. :)
    Mundus vult decipi
    Steve Davis
    Hank, are you suggesting I'm obsessive? My shrink assures me it's merely mild paranoia!
    "the sterility of the blind alley that is the selfish gene hypothesis"

    Funny, that is what I hear is the dominant (so fruitful) variant of population genetics, explaining everything from gene selection to kin selection. So you can certainly try to present a better theory, but you can't soundly accuse it of "sterility".

    Btw, it doesn't help your argument by being patronizing ("who can ... think"), if you, erhm, think about it.

    Gerhard Adam
    ...explaining everything from gene selection to kin selection.
    Actually it does nothing of the sort.  Genes cannot do anything to ensure their selection.  In fact, it is hardly plausible that genes should've evolved traits in species that would so radically diminish their ability to propagate (if that were their objective).  In the human being alone, there are at least 10 trillion sets of genes that are ultimately held "hostage" to the singular cell that may potentially transfer 50% of the genes for fertilization.  Doesn't sound like the most plausible explanation for such a strategy.

    However, even that aside, genes are irrelevant unless they are expressed, so while you can certainly argue that genes can get a "free ride" into the future by not doing any harm, you also can't claim that they've actually influenced the selection process either.  Epigenetics creates another problem in that some genes may never be expressed even though they are passed on, in which case they cannot be selected.  During mating, genes are not selected; traits are.  The difference is that few traits have a one for one correlation to a gene in any meaningful way, which also renders the notion of genic selection moot (since one would have to postulate that they cooperate to achieve their objectives, which is an even less tenable argument)

    That's only a mere glimpse at the difficulties.  You also mentioned kin selection, which becomes an interesting story, except for the fundamental problem that exists since there is no evidence that any species is actually capable of recognizing genetic kin.  In other words, there is no method by which genetic relationship is differentiable from mere proximity to establish the relationship.  Those that are raised together will behave as kin regardless of their genetic status.

    Even the proverbial eusocial insects don't adhere to that criteria when you examine the Argentinian fire ants which may house thousands of queens and workers that bear no genetic relationship to each other and yet their "alliances" work just as well as others where kinship is the "claimed" source.

    The most study of birds that was supposed to provide evidence for kin selection only had a 50% success rate in establishing that kin were actually being raised by the parents.  A spotty record at best.

    There's no question that these perspectives can be useful, but they hardly qualify as theories in any general sense.  They don't even hold up in the obvious case of human society.
    Mundus vult decipi
    Steve Davis
    Gerhard, I knew I'd hook a gene-centric sooner or later. (I wish I could get a coral trout to bite like that!) Thanks for cleaning him for me.
    Gerhard Adam
    I'm always a bit disappointed to see how gene-centric ideas are simply assumed to be true instead of anyone actually discussing the supposed evidence for it (the same with kin selection).
    Mundus vult decipi
    amorca
    Haha, thanks for let me feel that whatever happens some things will never change, it helps creating some kind of sense of security in a crazy world.
    The findings are interesting but not necessarily new ...

    http://jcb.rupress.org/content/107/2/481.full.pdf+html