Cell Membrane Dynamics: Surface Area, Shape, and Lipid Composition

Cell Surface Area to Volume Ratio and Membrane Shape

Fundamental Concepts of Cell Shape and Function

• Cells cannot exceed a maximum volume, but their shapes vary enormously.
• Cell structure defines cell function.
• Increasing the surface area of a cell without increasing the volume provides beneficial functions.
• The shape of a cell influences its function.
• As cells get bigger, the surface area changes more slowly than the volume.
• Changing the shape of a cell can have positive or negative consequences, depending on the cell's function.
  • Lung cells: Work best when they are flat and thin, like a pancake, because this shape facilitates the diffusion of gases across the cells between the blood and the lung cavity.
  • Unicellular algae: Microscopic cells that swim through water are better swimmers due to their nearly egg shape, which facilitates maneuverability and minimizes resistance through the water.
• A sphere is the optimal shape that reduces surface area relative to volume.
  • Example: Soap bubbles always wind up spherical.
  • Analogy: Racers on bikes or skis curl up as much as possible to reduce their surface area, which could slow them down.
• As the radius of a spherical cell increases, the volume increases much faster than the surface area.
• Fully understanding the relationship between surface area and volume is essential for understanding cells at the molecular level, as well as many higher levels of biological organization.

Mechanisms for Creating Large Membrane Surfaces

The Role of the Cytoskeleton

• The cytoskeleton is a collective term that includes all the proteins that provide support for the plasma membrane and give the cell its shape.
• It is similar to the metal framework of a tall building (Figure 7.15).
• Reorganization of the cytoskeleton can accomplish changing the overall shape of a cell.
  • Fluorescence micrograph of mouse skin cells shows microtubules stained green, actin stained red, and DNA stained blue (Figure 7.15A).
• Cells produce protein locomotive engines that can pull cargo along microtubules.

Increasing Surface Area with Microvilli

• Increasing surface area while keeping volume constant is a very common theme in biology.
• Example: Intestinal cells
  • The cells lining your intestine have small fingers, or microvilli, that increase the surface area of the cells while barely altering the total cell volume (Figure 7.15B-C).
  • With increasing magnification, the intestinal cell's crowded cytoplasm filled with its actin cytoskeleton can be seen.
  • Microvilli are one way molecules are used to increase the surface area of a cell.
  • Adaptive advantage: Intestinal cells display microvilli so they can pack more nutrient-absorbing proteins into their plasma membranes without increasing their cytoplasmic volume, which would slow diffusion through the cells.
• Evolution selected cells with wavy plasma membranes and organisms with such cells because they had an advantage over comparable cells with smooth cell membranes.

The Endoplasmic Reticulum (ER) Network

• The endoplasmic reticulum (ER) has a large surface area to volume ratio within the cytoplasm of eukaryotes.
• The ER is widely distributed as a series of interconnected tubes, rather than just one spherical vesicle.
• Adaptive features of ER shape:
  • Provides a large surface area on which ribosomes can land.
  • The interconnected tubes mean that proteins inside of the ER can diffuse throughout the membrane network without having to return to a central membrane hub near the nucleus.
  • Forms a weblike pattern because the microtubule tracks cross each other, which allows kinesin motors to move from one track to the next, regardless of the angle.
  • As the membrane tubes crisscross the cytoplasm, some will fuse, resulting in a network of interconnected tubes.

Lipid Composition and Membrane Shape

• The composition of lipids in a membrane affects the membrane's shape.
• Cells can alter their surface area to volume ratio by making membranes out of different lipids, many of which are synthesized in the smooth ER.
• Different membranes contain different ratios of lipids (Table 7.2).
• The chemical and physical properties of molecules determine cellular shapes and functions.

Experimental Investigation of Membrane Tube Formation

• Collaboration: Physicists from the Netherlands and biologists from Germany collaborated to study how cells build ER membranes.
• Methodology (Figure 7.16A):
  • Investigators produced large phospholipid vesicles.
  • Mixed vesicles with microtubules, a component of the cytoskeleton.
    • Microtubules are long polymers of the protein tubulin.
    • They function like molecular railroad tracks, frequently crisscrossing each other.
  • Added kinesin motor proteins.
    • Kinesin is one type of motor responsible for moving many proteins and organelles around inside cells (Figure 7.16B).
    • Kinesin can pull tubes of membranes along microtubule tracks, similar to pulling silly putty or bread dough into long, thin extensions.
• Observation (Figure 7.16C):
  • Kinesin proteins were incubated with a large vesicle composed of fluorescent lipids.
  • Over time, small tubes were seen extending from the large vesicle as the kinesin pulled out bits of membrane.
  • The volume of the vesicle plus the tubes remained essentially unchanged, but the total surface area grew rapidly as the tubes were pulled from the vesicle.

Mechanical Pulling Experiments and Lipid Composition

• Investigators mimicked the action of kinesin by mechanically pulling on the membrane to produce tubes similar to those produced naturally (Figure 7.17).
• They mechanically pulled membrane tubes a fixed distance away from the vesicle and measured the amount of force required to pull the tube.
• Findings:
  • When investigators changed the lipid composition of the large experimental vesicle, the diameter of the new tube being drawn out by kinesin changed (Figure 7.17).
  • Three different lipid compositions required different amounts of force to pull the tubes.
  • The three different tubes of membrane also had different diameters depending on the lipid.
    • "Normal" membrane vesicle (similar to ER membrane) pulled by a "bead" to form a membrane tube (Figure 7.17A) required a moderate force, forming a medium diameter tube.
    • "Relaxed" vesicle pulled to make a tube with a larger diameter (Figure 7.17B) required less force.
    • "Rigid" vesicle required more force and produced a small diameter tube.
  • Force measurements (Figure 7.17C):
    • "Rigid" vesicle: Peak force around $45-50\,pN$ for tube formation.
    • "Normal" vesicle: Peak force around $25-30\,pN$ for tube formation.
    • "Relaxed" vesicle: Peak force around $10-15\,pN$ for tube formation.
• Conclusion: By altering the lipid composition of their membranes, cells can control the surface area to volume ratios of their organelles, such as the ER.
  • Cells with the best lipid composition produce optimal surface area to volume ratios for the function of the rough ER and other organelles.

Cholesterol and Membrane Rigidity

• It has been known for years that cholesterol makes membranes more rigid (Figure 7.17C).
• Human plasma membranes contain more cholesterol than ER membranes.
• If cells had to pull cholesterol-rich ER membranes, they would need more force to pull the rigid lipid, and the diameter of the ER would be narrower than if the membrane were less rigid.

Spontaneous Membrane Shapes Driven by Lipids Alone

• Lipids alone are able to affect cell shapes (Figure 7.18).
• Biophysicists from Cornell University mixed two lipids in different proportions to produce spectacular shapes larger than typical human cells.
• The lipids were fluorescently labeled:
  • More rigid lipid appeared blue.
  • Less rigid, more fluid lipid appeared red.
• Vesicles contained assorted ratios of mixed lipids that self-assembled into shapes determined completely by the chemical and physical properties of the lipids.
• These vesicles were produced abiotically, yet they display shapes and movement associated with life.
  • Example: When the budded vesicle in Figure 7.18A was warmed by $5$ degrees, the blue (rigid) portion spontaneously severed itself from the red (fluid) portion (Figure 7.18B).
  • The rather bizarre and stable shapes in Figure 7.18D and E illustrate that membrane shapes can be determined at least in part by the lipids themselves and without input from proteins.
  • (Connections: Abiotic origins of life were explored in Chapter 4.)

Lipid Compositions in Eukaryotic Membranes

• Different membranes contain different ratios of lipids.
• The shape and therefore function of every organelle is determined in part by the lipids that constitute their membranes.
• Consequences of membrane rigidity/flexibility based on lipids:
  • If a membrane is too rigid, the resulting tubes would be very narrow, and more energy would be required to pull them during tube formation.
  • If a membrane were very flexible, not much energy would be needed to pull them into tubes, but the volume of the tubes would be large, which might be less efficient when trying to assemble multi-subunit proteins inside of the ER.
  • The "normal" mixture of lipids in ER membranes produces a balance of the right diameter tube at an energy cost that is appropriate (e.g., for assembling multi-subunit proteins).

Lipid Composition (percentage of total lipids) of Membranes in Eukaryotes (Table 7.2)

• Lipid Name
  • _Rat liver ER_
    • Phosphatidylcholine: $58$
    • Phosphatidylethanolamine: $22$
    • Sphingomyelin: $3$
    • Phosphatidylinositol: $10$
    • Phosphatidylserine: $3$
    • Phosphatidic acid: $0$
    • Cholesterol: n.d.
  • _Rat liver plasma membrane_
    • Phosphatidylcholine: $39$
    • Phosphatidylethanolamine: $23$
    • Sphingomyelin: $16$
    • Phosphatidylinositol: $8$
    • Phosphatidylserine: $9$
    • Phosphatidic acid: $0$
    • Cholesterol: n.d.
  • _Rat liver Golgi_
    • Phosphatidylcholine: $50$
    • Phosphatidylethanolamine: $20$
    • Sphingomyelin: $8$
    • Phosphatidylinositol: $12$
    • Phosphatidylserine: $6$
    • Phosphatidic acid: $0$
    • Cholesterol: n.d.
  • _Mouse skin plasma membrane_
    • Phosphatidylcholine: $43.0$
    • Phosphatidylethanolamine: $16.1$
    • Sphingomyelin: $12.2$
    • Phosphatidylinositol: $7.6$
    • Phosphatidylserine: $6.4$
    • Phosphatidic acid: $0.0$
    • Cholesterol: $13$
  • _Yeast inner mitochondria_
    • Phosphatidylcholine: $38.4$
    • Phosphatidylethanolamine: $24.0$
    • Sphingomyelin: $0.0$
    • Phosphatidylinositol: $16.2$
    • Phosphatidylserine: $3.8$
    • Phosphatidic acid: $1.5$
    • Cholesterol or diphosphatidylglycerol: $16.1$
  • _Yeast outer mitochondria_
    • Phosphatidylcholine: $45.6$
    • Phosphatidylethanolamine: $32.6$
    • Sphingomyelin: $0.0$
    • Phosphatidylinositol: $10.2$
    • Phosphatidylserine: $1.2$
    • Phosphatidic acid: $4.4$
    • Cholesterol or diphosphatidylglycerol: $5.9$
  • _Yeast inner nuclear_
    • Phosphatidylcholine: $44.6$
    • Phosphatidylethanolamine: $26.9$
    • Sphingomyelin: $0.0$
    • Phosphatidylinositol: $15.1$
    • Phosphatidylserine: $5.9$
    • Phosphatidic acid: $2.2$
    • Cholesterol or diphosphatidylglycerol: $1.0$
    • n.d. means not determined.
    • Percentages do not add up to $100$ because some types of lipids were not quantified.

Integrating Concepts

Secretory Vesicles and Lipid Composition

• Secretory vesicles containing epinephrine would be expected to contain lipids that can produce spheres of small diameter.
• A small diameter produces a large surface area compared to volume.
• Based on the data, rigid lipids produced tubes with smaller diameters and required more force.
• Therefore, secretory vesicles would be predicted to contain more rigid lipids to achieve the desired small diameter and large surface area to volume ratio.

Membrane Curvature and Protein Localization

• A $2009$ Science abstract by Kumaran, et al., illustrated that bacterial proteins preferentially sort to areas within a cell based on the curvature of membranes.
• It is currently understood that the composition of bacterial membrane lipids (which determines membrane shape) and the physical curve of the membrane are intricately related to each other in determining protein localization.
• The physical property of membranes (curvature) played a role in the subcellular localization of proteins.

Overall Summary of Cell Shape and Function

• Cells alter their surface area to volume ratio, which affects the cell's function, through new components like membrane lipid composition.
• Lipids significantly influence the shapes of cell membranes.
• The composition of lipids and the resulting shape are all part of the structure/function relationship of cells.
• Cell shape determines its function, and its shape is affected by the proteins and lipids in each cell.