The Future of Cell Biology - Part I - Organellar Shape

OK this is an attempt to revive the blog. This entry is inspired by a talk given about a month ago by my mentor, Tom Rapoport. I hope that it will be the first of a series of posts where I ramble on about what we don't know. In each post I'll discuss a topic that remains mysterious. I'll try to point out what we don't fully comprehend and add my two cents. Today's topic will be organelle shape.

Look inside any eukaryotic cell and you'll lots of little membranous organelles whizzing around. These membranous structures play crucial roles in various cellular activities. Very often their shape contributes to their function.

Why?

Think about surface area - the more membrane an organelle has, the more/less efficient certain processes are.

Think about organelle contacts. Mitochondrial membranes may need to be close to certain portions of the endoplasmic reticulum (ER) in order to exchange molecules.

Think about the movement of vesicles between different compartments. The Golgi is constantly losing and gaining membrane vessicles which pinch off and fuse with each Golgi stack. These vessicles travel between the Golgi and other organelles such as the ER and the endosomes. All this vesicle exchange is dictated in large part by organelle morphology and distribution.

Think about transport. It may be helpful that an organelle is a rod in order for it to be translocated up and down neuronal projections.

And think about other functions. For example, the nucleus shape may influence the spatial arrangement of chromosomes and thus affect gene expression. Many cells have bizarre looking nuclei, and almost nothing is know as to how the nuclear shape is altered and how this contributes to proper cellular function .

So the central questions of how and why organelles are shaped are relatively fertile ground within cell biology.

To get an idea about organellar morphology, look in any cell biology textbook and you'll find examples of incredible subcellular structures. Or better yet peruse the American Society for Cell Biology Image & Video Library. If you think that these shapes are just a product of the physical laws governing membrane curvature and turgor pressure, you are missing the point.

For example take mitochondria. Here's an image of the prototypical mito from Don Fawcett's book The Cell. (BTW you can browse through the entire book online at the ASCB website)

As you can see mitos have two membranes each of which having different morphologies. The outer membrane tends to be rod shaped (mitochondrion is Greek for thread+granule) while the inner membrane is highly convoluted. These convolutions of the inner membrane, or cristae, increase the membrane size. This increased size allows for more enzymes which reside in the membrane and convert chemical energy into a proton gradient across the inner membrane that in turn gets converted into useful energy (i.e. ATP).

So what generates the shapes of the two membranes? We don't have a good answer yet. But looking at other versions of this fantastic organelle, you get the sense that there are many proteins that promote very specific membranous conformations. For example here are mitos from sertoli cells (these are the support cells of the testes):

You'll note that the inner membrane forms some regular "crystalline" pattern. And then there are mitos with pyramidal inner membrane tubes. Here's an example from a glial cell from hamster brain:

But it is not just the inner membrane - the outer membrane can take on may different morphologies. You can have long skinny mitos, spherical mitos, flat mitos ... you name it.

So what are the components that dictate these shapes? This is the problem that needs attention.

1 - You need proteins that help bend membranes. More and more of these are discovered every year. Some like clathrin act as a scaffold on the membrane to actively bend the surface. Others like reticulons sit in the membrane and probably form mini scaffold structures. And there are yet other proteins, like those that contain "bar domains" that sit at the interface between the membrane and the extra membrane space.

2 - You need proteins that regulate membrane to membrane distances. One surprising feature of organelles is that very often then spacing between membranes is very regular. This is probably achieved by these long proteins that span these membrane-membrane spaces. A good example of this type of protein is the golgins. These giant proteins reach across from one membrane of the Golgi to the next and are thus thought to allow the Golgi stacks to stay together with a regular spacing. (To the right is a nice image of Golgi stacks taken again from Fawcett's book The Cell.)

3 - You need to take into account the cytoskeleton. These long polymers extend throughout the cytosol and dictate where the organelles are positioned. But the cytoskeleton is likely to have other indirect effects on organelles. Throughout the last 15 years it has been clear that cytoskeletal proteins act as signaling molecules. For example, when a microtubule disassembles a slew of signaling molecules get locally activated. When the microtubule repolymerizes other molecules become active. These molecules are known to interact with other cytoskeletal elements, such as actin, and vessicles ... they probably also interact with organelle shaping proteins. And then there are all the unstudied cytoskeletal elements. Did you know that septins might interact with the ER? And there is a ton of spectrin on the Golgi. And I bet that these organelles may have as yet undiscovered filaments bending and shaping them from within ... why not?

4 - Regulators of membrane composition. The lipid content, the protein content and the osmotic and chemical gradients across membranes are all likely to affect membrane morphology. Some studies have been performed on lipid microdomains and how changes in lipids can act to bend membranes, but more work needs to be done.

5 - Dynamics. Morphology, just like other biological functions requires mechanisms that cope with a changing environment. Sometimes the organelle must stay static, other times it must change as well. From what we know this will require dynamic processes. Membranes will always be actively bent, streched and molded. If you think for one second that organelles and their shaping machines are static, think again.

OK folks that's all I have time for. Add your two cents in the comment section.