A Rice University graduate student has identified a new subcompartment within peroxisomes, cellular organelles involved in metabolism, and suggested they may play important roles in managing fatty acids and offer a window into a range of disorders.
First observed in 1954, peroxisomes break down long-chain fatty acids and form compounds used elsewhere in the cell during metabolism. They affect cancer and aging as part of their work in the immune response and balancing levels of oxidation agents, which can damage cell structures at high concentrations.
Years before his discovery was published in a paper in Nature Communications, Zachary Wright was investigating the formation of peroxisomes at Rice. He genetically modified a sample of peroxisomes to produce fluorescent proteins and was surprised to see that they contained numerous inner membranes, which were later dubbed intralumenal vesicles, or ILVs. In his images, ILVs lit up in a bright green, while the rest of the peroxisome were colored magenta.
Measuring in at roughly 1 micrometer or less wide, the peroxisomes were not known to have additional structures beyond its outer membrane — besides a temporary crystalline core that can form with a high concentration of some enzymes.
“(Peroxisomes) were supposed to just be a simple single-membrane sac, and instead I saw these membranes inside of them,” Wright said. “I remember I thought it was wrong, and I thought I was just looking at something else.”
After confirming that his observations weren't experimental artifacts and convincing his professor and coauthor, plant biologist Bonnie Bartel, Wright found that scientists noticed ILVs several times in the 1960s and 1970s. But at the time, researchers didn't look closely at them, because of preoccupation on other matters and limited microscope technology .
Wright benefited from studying cells of Arabidopsis thaliana, a flowering plant native to Europe, Asia and Africa with peroxisomes dozens of times larger than mammalian cells and easier-to-spot ILVs. The unusually large organelles are thought to handle the large amounts of fat that the plants’ seeds store until growth begins. (Widely used in plant biology and genetics, Arabidopsis thaliana was the first plant to have its genome mapped back in 2000.)
The ILVs appear to be constructed from the peroxisome’s outer membrane, according to Wright and Bartel. They took time-lapse photos of peroxisomes in a maturing seedling cell, and they observed peroxisomes shrink as they fill with more ILVs. Another test with fluorescent reporters showed only some ILVs glowing, leading the researchers to suggest that the membranes of subcompartments within a single peroxisome may contain different proteins.
As for the subcompartments’ functions, the researchers believe that they aid in metabolism by importing fatty acids into the peroxisome — and preventing the hydrophobic compounds from haphazardly bonding to cell membranes in a water environment. If accurate, this could explain why peroxisomes evolved to break down fats when mitochondria already could, they said: Mitochondria struggle to safely metabolize fatty acids with long chains, which are more hydrophobic than short ones, while the ILVs help peroxisomes process them more effectively.
The authors said that understanding the functions of ILVs, and how their functions get distorted by mutations, could shed light on cancers and peroxisomal disorders, a category of rare hereditary conditions stemming from defects in peroxisomes. These include X-linked adrenoleukodystrophy, which can degrade brain function and lead to death at a young age, and Zellweger spectrum disorders, which can create neurological issues, abnormal facial features and other organ defects.
Wright said he plans to continue his initial research pursuit into peroxisome formation but that his findings open up a lot of new questions about how the organelles work and the role that ILVs play.
“This is the kind of result that is going to open up a lot more avenues than our lab can pursue alone,” Wright said.
The article, “Peroxisomes form intralumenal vesicles with roles in fatty acid catabolism and protein compartmentalization in Arabidopsis,” was published Dec. 4 in Nature Communications. The authors of the study were Zachary Wright and Bonnie Bartel, Rice University. The lead author was Zachary Wright.