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Stars
are the largest fusion reactors around,
and organisms do use
some of the energy our Sun
produces by joining two hydrogen atoms
into a
helium atom - remember photosynthesis? Fission reactors are
closer to home, but
are much less efficient -- and can melt down
and
kill us all. Cellular fission and
fusion are about joining
and
splitting things as well, just without the
release of energy.
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In the typical picture of a working cell, you would see millions of vacuoles traveling around, joining together and splitting off from organelles. The general proposition is that a bag of stuff fuses
(joins) or fissions (separates) from another bag of stuff.
In physics, fission and fusion can be sources of great energy, but in cells they usually require an input of energy. If the processes were the same, we could run the world’s electronics on biology power – a true cell phone!
In physics, fission and fusion can be sources of great energy, but in cells they usually require an input of energy. If the processes were the same, we could run the world’s electronics on biology power – a true cell phone!
Fusing and fissioning are easy for vacuoles, they have one
membrane. But the mitochondria and chloroplasts we have been looking at for the
past few posts have very specific, double membrane structures. The outer
membrane and inner membranes form a intermembrane space that is crucial for
their function, and the inner membranes have specific forms and structures that are necessary to make carbohydrate or ATP.
Wouldn’t fusing or splitting these organelles destroy the
membrane structures needed to maintain their functions? Indeed, the typical
cartoon of the cell shows individual mitochondria or chloroplasts floating
around in the cell, doing their jobs, but not interacting with the other
organelles or with each other.
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The
structure pictured in green is, believe, it or not, the
mitochondrion
of a fibroblast (fibro = fiber and blast =
sprout)
cell, one that makes connective tissue. This doesn’t
look
much like the mitochondrion in the biology books,
does it?
The different strands join together and separate
constantly.
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All these features (shape, communication, movement,
fusion, fission, and exchange) are dynamic, meaning that they change with time
and are regulated. First recognized as a regulated process about 10 years ago,
this has spawned a new line of research called mitochondrial dynamics.
Changes in morphology are also involved in progression
through the cell cycle. A 2009 study showed that in cultured cells, the
mitochondria must fuse together into branched networks in order for the cell to
enter the phase when it replicates its DNA. Now it appears that this changing
mitochondrial morphology is important for other shifts in cell fate. The same
group that conducted the 2009 study above showed in May 2012 that mitochondrial fusion and fission are important for oogenesis differentiation (the changes an egg goes through to become different types of cells) in fruit fly egg chambers, implying their importance
in differentiation of other cells too.
It appears that fusion and fission help to maintain the
correct number of mitochondria, but also work in the preservation of
mitochondrial function. Defective proteins can be kicked out if there are
normal proteins to replace them. Fusion of mitochondria can provide these
normal proteins. In other instances, low oxygen or low carbohydrate
concentrations can bring fission and fusion so that the mitochondria can share
nutrients and prevent their own degradation.
Most importantly, defective mitochondrial DNA (mtDNA) can be minimized by combining
or being replaced it with normal DNA from functioning mitochondria. In most cases,
recombination of DNA serves to increase genetic diversity, but with mtDNA it
seems the opposite effect is desired. Recombining and exchanging DNA serves to
maintain a single uniform genome for all the mitochondria; fusion can preserve
the integrity of the mitochondrial genome. Mutations or defects in either
exchange, fission, or fusion systems result in poor mitochondrial function and
identifiable diseases.
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People
with Charcot-Marie Tooth have very high
arches,
and are most often double jointed. Would
you
enjoy having your knees bend the other
direction?
I can tell you from personal experience,
that
double jointed people are very hard to wrestle
against.
They can slip out of whatever hold you try
on them.
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If the
fusion of mitochondria is defective, a disease called Charcot-Marie-Tooth type 2a may
result. This is a neuronal
degenerative disease that usually affects the lower extremities more than the
arms. Most cases are caused by defects in the cells that surround the neural
axon (the long projection between the cell body and the connection point to other
neurons), but in type 2a, the defect is in the axon, specifically the inability
of mitochondria to fuse. Therefore, fusion must be important.
In Huntington’s
disease, there is too much mitochondrial fission. Huntington’s chorea
(chorea = dance, patients with this disease develop large uncontrollable
movements that make it look like they are dancing). The cause is an expansion
in the huntingtin gene (yes, I
spelled it right); a three DNA base repeat (CAG) is mutated and becomes
repeated too many times. This affects the function of the huntingtin protein.
The age of onset and speed of progression are related to how expanded the
triplet repeat is. As of today, this autosomal
dominant genetic disease (only need to inherit one mutant gene for it to
occur) is untreatable and fatal.
However, the mechanism by which this mutation causes neuron
degeneration is just becoming clear.
A 2010 study indicated that the mutant huntingtin protein interacts with
the proteins that control mitochondrial fission and makes them overactive. Too
much fission disrupts mitochondrial functions and the neurons become defective
and then die.
Even more important, in terms of numbers of people affected,
is the link between reduced mitochondrial fission and Alzheimer’s disease.
Scientists know that it was the build up of amyloid protein that promotes
neuron degeneration, but until recently, they didn’t know how it was occurring.
It turns out that the plaque proteins can stimulate nitric oxide production,
which then damages the fission proteins of the mitochondria.
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DRP1
proteins are important for the fission of a
mitochondrion
into two mitochondria. They oligomerize
(join
together in groups) and pinch the mitochondria
apart.
Nitric oxide can damage the DRP1 proteins – so
no mitochondrial
fission.
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This is
huge news because preventing this nitric oxide damage might be a way to
slow or stop Alzheimer’s progression. This is a difficult area of research,
since nitric oxide is important in many biochemical pathways; just shutting
down nitric oxide production everywhere in the body would lead to defective
hair growth, blood vessel pressure control, abnormal blood clotting and
atherosclerosis, ……oh, and Viagra wouldn’t work either.
The movement of mitochondria within cells is also crucial
for their function. The longest cells in your body are your motor neurons. A
single cell can be several feet long. Your mitochondria must get to where
they are needed along the axon of the
neuron, and this requires regulated transport and communication.
Defective transport is one outcome during
Charcot-Marie-Tooth type 2a defective mitochondrial fusion and in
overstimulation of mitochondrial fission in Huntington’s disease. In addition,
defective axonal transport of mitochondria may turn out to be an important
early defect in Alzheimer’s disease. In fact, defective transport of
mitochondria may play a role in Parkinson’s disease, amyotrophic lateral
sclerosis (Lou Gehrig’s disease) and other neurodegenerative diseases that
involve defective mitochondrial fusion and fission.
Why might this be….. I’m not sure, but here is a guess. Defective
fusion or fission leads to defective function – defective function leads to
reduced ATP formation – reduced ATP results in defective energy-requiring
functions of the cell, like transport of mitochondria from one place to
another. I have no evidence for this, but it is a logical, testable hypothesis.
It could be that defective transport is an effect, not a cause, of these
diseases -at least in part.
 |
Two of
our more famous Parkinson’s patients;
Muhammed
Ali and Michael J. Fox. Float like Marty
McFly and sting like a bee? |
For
Parkinson’s disease, a 2009 study showed that defective mitochondrial
transport occurred due to dysfunction in the fusion/fission system, independent
of changes in the ATP level. However, ATP production is not the only function
of mitochondria. They also work in regulating the amount of calcium in the
cell, and altered calcium levels can lead to disruption of the cytoskeletal
transport mechanisms. Maybe I need to tweek my hypothesis; it is
fusion/fission-mediated defects in several mitochondrial functions that
then cause axonal transport changes that are noted in many neurodegenerative
disorders. Now design an experiment to test it - this is how scientists go
about their work.
So we see that the mitochondria are not static, they are
changing all the time and that these changes are crucial for their function and
integrity. Here is our exception in the similarities of chloroplasts and
mitochondria. It would seem, at least based on current evidence, chloroplasts
are relative loners.
This is not to say that can’t be dynamic. We have seen that
chloroplasts have a definitive inheritance pattern, either maternal or
paternal, and they will fight to maintain this pattern. Chloroplast fusion has
been most often described in the zygote
(initial cell formed by fusion of the gametes during fertilization, from Greek
zygota = joined or yoked together) of algae. In these cases, which are still
rare, the chloroplast genome of one of the two fused organelles will be
degraded. Fusion of other chloroplasts, as in mature plant cells, either does not
occur or has not been studied, because I can’t find any publications describing
it.
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These
are examples of the dynamic activities of chloroplasts.
Stromule
connections can be formed between chloroplasts for
the
passage of organelle contents. They are usually 0.5 microns
in
diameter (1/500,000 of a meter) and can be found in all types
of
plastids. Their function – not completely known yet.
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On the
other hand, chloroplasts aren’t complete loners either. As far back as the
1960’s there were reports saying that chloroplasts might have certain
connections at certain times. More recent studies indicate that small
connections can be formed between chloroplasts, often called tubular
connections or stromules. It is
interesting that stromules can be formed between chloroplasts and mitochondria.
It is believed that this is one way the plant cell keeps these two organelles
close to one another, since their functions, products, and by-products are so
interrelated.
You might ask why the mitochondria and chloroplasts that have so
much in common differ in their relative dynamic properties. They were both
once free organisms that had to have lots of interactions with other members of
their species, but only the mitochondria seemed to have preserved it. Next week, we will look into how this
mitochondrial dynamism is even more crucial organism survival – by regulating
cell death. Believe it or not, cells have to know how to die well.
Kasturi Mitra, Richa Rikhy, Mary Lilly, and Jennifer Lippincott-Schwartz (2012). DRP1-dependent mitochondrial fission initiates follicle cell differentiation during Drosophila oogenesis J Cell Biol DOI: 10.1083/jcb.201110058
For
more information or classroom activities on mitochondrial dynamics or cellular
differentiation, see:
Mitochondrial
dynamics –
https://research.uiowa.edu/arra/project/176
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