Our bodies are made of cells. Each cell is a soup of smaller components, all working together to execute the body’s various functions. Perhaps the most well-known of these components are proteins — long chains of amino acids that cells make with instructions from the DNA. When the DNA changes, the cell is able to make new proteins, sometimes with new functions, and in this way proteins are understood to be an integral part of evolution.
But new research is finding that this may also be a narrow view that misses other ways in which we evolve.
“Lipids make up to 30% [of the dry weight] of living cells. But people think of them only as shells,” Sven Gould, an evolutionary cell biologist at the Institute for Molecular Evolution in Düsseldorf, said.
Time for an updated view
Lipids are fat in cells. A textbook image of the cell membrane (which is what Gould meant by “shell”) shows proteins jostling in a bed of lipids. Scientists know a lot about these membrane proteins. About 25% of all human proteins are estimated to be located in the membranes. They carry out many functions: as receptors, they bind to specific molecules outside the cell; as channels, they allow specific molecules to enter and leave the cell; and as catalysts, they help speed up chemical reactions.
On the other hand, scientists’ understanding of lipids is limited to their role as a packing material, as things that hold proteins. In fact, they’re often imagined to be arranged in a homogenous layer made of round heads and long, flowy tails — readymade for proteins to just be dropped on.
A study published recently in Nature Communications from Swasti Raychaudhuri’s lab at the CSIR-Centre for Cellular and Molecular Biology, Hyderabad, challenges this view.
The RC1 complex
The team’s study focused on a group of membrane proteins called respiratory complex 1 (RC1). RC1 and other similar complexes are essential for cells to produce energy when the body breathes oxygen. They are found in the mitochondrial inner membranes of all eukaryotic cells that require oxygen to respire — including ours.
RC1 is the largest of these respiratory complexes. In humans, it is an obtuse-angled complex made of 44 proteins in humans. Some of the proteins are made in the cell’s cytoplasm and some inside the mitochondria. They find their way to the mitochondrial inner membrane to form the complex.
To study RC1, the scientists divided it into three parts: one that faces the inside of the mitochondria and catalyses reactions for energy production during respiration; one that moves through the lipid-rich mitochondrial inner membrane and acts as a canal for hydrogen ions; and one that extends into the space between the inner and outer mitochondrial membranes and whose exact roles are not yet understood.
Since RC1 is essential for respiration in living cells, mutations in it are expected to cause diseases. When looking for known RC1 mutations associated with diseases, the research team found something unexpected in the inter-membrane RC1 part: half of the mutations were in regions that interact with lipids in the mitochondrial membranes.
Proteins and lipids together
Upon investigating further, the researchers found that the inter-membrane parts of RC1 as well as lipids in the membranes are not the same in all life forms. Plants and animals have different versions. Using precise biochemical techniques, the researchers examined the lipid variety in cells and found that plant lipids have a kinkier structure than their animal counterparts. They attributed this to plant lipids being rich in polyunsaturated fatty acids.
Using computational models, the team then compared the affinities between inter-membrane proteins of human and plant RC1s and a human and plant lipid called cardiolipin. It is the most prominent lipid found in the mitochondrial membranes.
They found that the proteins in human cells preferred human lipids over plant lipids, and vice versa. Similarly, in cultured cells, when team members inserted a part of plant RC1 that faces the lipids in the membranes into human mitochondrial membranes, they found that the complex disintegrated. In other words, the RC1 complex needs cardiolipin from organisms of the same kingdom for it to maintain its physical integrity. The team concluded that certain details in the structures and composition of lipids decide which proteins can exist with them.
Going a step further, the researchers have suggested that membrane lipids have evolved over time to suit the survival needs of different organisms. The kinkier tails of plant lipids offer greater structural flexibility in the membranes. This could have been because plant-like organisms have faced variegated environmental stresses through history, like drought, heat, and salinity, and benefit from having structurally flexible lipids.
Importantly, the proteins would then have had to co-evolve with the lipids to function correctly.
Need for new tools
In fact the new study may be the first to support the idea of lipid-protein co-evolution in mitochondrial membranes. Of course, it also holds up previous research that has demonstrated how lipids and proteins cross-talk in other membranes inside cells.
“Most labs study the roles of DNA, RNA, and proteins in evolution because a large community has grown around it,” Gould said. “However, evolution happens through all kinds of molecules that make up living cells and we need to study them.”
Not just in evolution: the study also opens up the possibility of understanding human health better. Drugs like statins are commonly used to control cholesterol — another prominent lipid — in cells. As scientists develop a fuller understanding of the roles lipids essay, they may assess and optimise the long-term use of substances like statins. The role of lipids in controlling the entry of pathogens into cells also demands attention.
However, these studies also require more sophisticated biological tools that don’t yet exist. Lipids are more complex molecules than proteins. While proteins are well-understood polymers consisting of 20 amino acids arranged in different ways, lipids are made of fatty acids that vary in length and chemical composition both. Their composition in particular is only partly controlled by an individual’s genes; the rest is influenced by diet and other environmental factors. Existing tools to study lipids also fall short when accounting for these complexities.
“It is extremely difficult to reconstitute lipids in labs. And membrane proteins are the toughest. But computational methods have developed faster than the biochemical tools,” Gould added. “Will these inspire more scientists to take up lipid biochemistry? That remains to be seen.”
It’s nevertheless clear that textbook images and the scientific imagination both need to change their attitudes towards membrane lipids. LDL, HDL, triglycerides, and cholesterol are already part of our daily consciousness. Studying these and other lipids further can thus help improve medical care as well as enhance our view of evolution. It’s a win-win.
Somdatta Karak, PhD heads science communication and public outreach at the CSIR-Centre for Cellular and Molecular Biology, Hyderabad.
Published – April 24, 2025 05:30 am IST
