Cell Membrane Lipids: More than Fat Chance
Reporting in Nature, Joost C.M. Holthuis and Anant K. Menon provide a fairly detailed survey of the fascinating world of lipids: the building blocks of membranes. The paper, "Lipid landscapes and pipelines in membrane homeostasis," discusses, with illustrations, a symphony of processes and players that maintain the integrity of the cell and its organelles.
If you've been told that lipids (fatty acids) in cells self-organize into membranes, you've heard a half-truth. Yes, lipids will spontaneously form layers and bilayers due to their hydrophobic chains and hydrophilic heads, but membranes need to do much more than wall in the cell or its organelles. They also have to control which proteins and other molecules are allowed to pass in or out. Some organelles need looser or tighter membranes. And all need to respond to signals with special sensors.
Here are a few highlights from this paper. The high level of design is obvious:
- Variety. There are many different kinds of lipids. "The organelles along the secretory pathway have major differences in lipid composition that help to shape their specialized tasks," the authors say. For instance, phospholipids (the most abundant) form narrower membranes than sphingolipids. Due to the properties of specific lipids, some membranes will curve into a cone, some will curve into a cylinder, and others into an inverted cone shape. Specific lipids influence the fluidity, thickness and packing density of the membranes they comprise.
- Electrostatics. Some membranes carry a charge, due to the composition of the lipid molecules in the "head" of the molecules. The charge is functional: for instance, "The endoplasmic reticulum (ER) has a thin bilayer, loose lipid packing and neutral cytoplasmic surface charge adapted for its biogenic function," while "The plasma membrane (PM) has a thick bilayer, tight lipid packing and negative cytoplasmic surface charge adapted for its barrier function." The charged lipids are spaced within the membrane to provide just the right amount of charge; this charge density is tightly controlled.
- Physical properties. Membranes can be stiffened or loosened in several ways. One is by using saturated or unsaturated fats. Saturated lipids bind more tightly together, forming stiffer and less permeable membranes. Sterols inserted between the lipids can also affect the thickness and packing density of the membrane; "Thickness is promoted by acyl-chain length and sterols, which order and stretch the acyl chains." The properties are carefully regulated, because defects can be disastrous. For instance, "an imbalance between saturated and unsaturated phospholipids readily affects ER biogenic activity, inducing a stress response that can trigger cell death."
- Manufacture. The production of lipids and sterols is complex! The authors show a flowchart of chemical pathways for the manufacture of cellular lipids. It reveals a multitude of proteins, enzymes, and cofactors that take part in regulated, rate-limited production lines. Some of the steps occur in the cytosol, many in the ER, some in the mitochondria. Final packaging and delivery of sphingolipids takes place in the Golgi body. "Thus, the Golgi defines a demarcation line between two broad membrane territories with distinct physical and functional features."
- Sensing. Even in "simple" bacteria, membranes are studded with sensors that can produce downstream effects. For instance, "Thermosensor DesK is a histidine kinase acting at the top of a regulatory cascade controlling the synthesis of unsaturated fatty acids in Bacillus subtilis." A drop in temperature triggers a cascade of effects that includes feedback to the genes, regulating lipid manufacture. There are stress sensors, packing defect sensors, sterol excess sensors, curvature sensors, and more.
- Pipelines. Newly manufactured lipids from the ER need to be delivered to where they're needed. "Newly synthesized lipids are exported from the ER as components of secretory vesicles, or through pipelines operated by cytoplasmic lipid transfer proteins (LTPs)," the authors say. "The latter mechanism is crucial for supplying ER lipids to mitochondria and other organelles that are not connected by vesicular trafficking but rely on lipid import for proper function." It's notable that delivery continues unabated when vesicular traffic is shut off. This led the authors to focus on the lipid pipelines, which they determined are the "key to lipid homeostasis" (dynamic equilibrium). Their cartoon drawing shows a dizzying array of donor and acceptor machines that take part in the complex delivery system.
- Cross-communication. Membranes talk to each other. The ER membrane is in touch with the plasma membrane through a series of machines and chemical pathways, so that the manufacturing plant knows what the remote site needs for repairs and growth. After discussing some details, the authors say, "Thus, a number of pipelines intersect to ensure that sphingolipid precursors reach the trans-Golgi in synchrony with sterol arrival, allowing a fundamental transition in the lipid landscape that divides the secretory pathway in early and late membrane territories."
- Health and balance. In their final subsection, the authors discuss what happens when things go wrong. "Numerous links between lipid imbalances and human pathologies underscore the importance of membrane lipid homeostasis," they begin, then they "focus on two examples that highlight the physical principles of lipid organization in early and late membrane territories in the context of liver disease." The results of failure can be severe. Obesity, diabetes, cholestasis are just a few consequences when the normally balanced system has a breakdown.
It should be obvious that membrane construction and maintenance is highly complex and finely tuned. Some evolutionists focus only on the self-organizational properties of lipids, thinking that simple membranes might have surrounded RNA molecules or the first proteins during the origin of life to protect them from dilution or damage. As we have seen, though, even in bacteria the level of complexity is high. The first cell could not just "wall in" its lucky molecules. Cells need to take in nutrients and excrete waste. A beginning cell membrane could not, furthermore, just "leak" to pass material in and out by osmosis. A cell needs active transport to work against concentration gradients. Without the sensors, pathways, and gateways provided with the lipid membranes, to say nothing of a genetic information system controlling them, a simple membrane would be a death trap.
In their concluding "Outlook" subsection, the authors mention a surprise that they think is a portent for more discoveries:
Surprisingly, some recently identified lipid composition sensors have turned out to be dual function proteins, with their second function mediating seemingly unrelated processes such as protein quality control and vesicular trafficking. This reinforces the concept that membrane lipid homeostasis is integral to a wide range of cellular processes. Because the dual roles of these proteins were not predicted, it seems likely that other examples of 'moonlighting' lipid composition sensors will be discovered.
Indeed, much remains to be discovered about the world of lipid membranes. It would seem that intelligent design has an opening here, because the authors had only a quick just-so story to give in favor of Darwinian evolutionary theory:
The lipid composition of cellular organelles is tailored to suit their specialized tasks. A fundamental transition in the lipid landscape divides the secretory pathway in early and late membrane territories, allowing an adaptation from biogenic to barrier functions. Defending the contrasting features of these territories against erosion by vesicular traffic poses a major logistical problem. To this end, cells evolved a network of lipid composition sensors and pipelines along which lipids are moved by non-vesicular mechanisms. (Emphasis added.)
How did that happen, by fat chance? Since they could say no more about evolution, and the bulk of the paper considered the "elegant" systems at work in membranes, it appears that intelligent design is best positioned to understand the players and processes that remain to be elucidated. The expectation of design is a good motivator for research.