Peroxisomes are organelles found within the cytoplasm of nearly all eukaryotic cells. These small, single-membrane compartments house enzymes that perform specialized oxidative reactions, including the breakdown of very long-chain fatty acids and the synthesis of lipids called plasmalogens. They also detoxify harmful substances by metabolizing molecules and neutralizing reactive oxygen species, such as hydrogen peroxide. For a cell to maintain its metabolic balance, it must produce these organelles through a process known as biogenesis to ensure a sufficient population of functional peroxisomes.
Pathways of Peroxisome Formation
The creation of new peroxisomes occurs through two primary, interconnected pathways. One route is de novo synthesis, where new peroxisomes originate from the endoplasmic reticulum (ER). Specific proteins required for peroxisome formation are inserted into the ER membrane, where they cluster and cause the membrane to pinch off. This forms an immature vesicle known as a pre-peroxisome. This initial vesicle is an empty container, ready to receive the enzymes and proteins that will make it a functional organelle.
This budding from the ER provides the building blocks for the peroxisomal population. The process is regulated to ensure vesicles are formed with the correct initial membrane proteins to guide their development. This pathway is important in cells that have lost all pre-existing peroxisomes, allowing the cell to regenerate its peroxisomal compartment.
The second pathway is the growth and division of pre-existing peroxisomes. An existing peroxisome increases in size by importing proteins and acquiring lipids from the cytosol. Once it reaches a certain size, the peroxisome constricts and divides into two daughter peroxisomes. This fission process is the primary mechanism for cells to rapidly increase their number of peroxisomes in response to metabolic demands.
The two pathways are not mutually exclusive and work together. The de novo pathway can establish the initial peroxisomes, while the growth and fission pathway allows for their proliferation and maintenance. This cooperation ensures the cell can dynamically adjust its metabolic capacity.
Import of Matrix and Membrane Proteins
A peroxisomal vesicle must be filled with enzymes and populated with membrane proteins to become functional. These proteins are synthesized in the cytosol and delivered to the peroxisome after they are made. This process relies on targeting signals within the proteins, which act like postal codes to ensure they reach the correct destination, where they are recognized by a dedicated import machinery.
Enzymes destined for the peroxisome’s interior, or matrix, have two main Peroxisomal Targeting Signals (PTS). The most common is the PTS1 signal, a short amino acid sequence at the end (C-terminus) of the protein. A less common signal is the PTS2, a longer sequence at the beginning (N-terminus) of the protein. These signals direct enzymes like those that break down fatty acids or neutralize hydrogen peroxide.
Proteins embedded within the peroxisomal membrane, known as peroxisomal membrane proteins (PMPs), require their own targeting signals. These signals differ from the PTS1 and PTS2 signals used for matrix proteins. The targeting information for PMPs is contained within a stretch of the protein near a transmembrane domain, which anchors it into the membrane. This ensures PMPs are correctly inserted to perform functions like transporting molecules and anchoring import machinery.
This system of distinct targeting signals allows the cell to control the peroxisome’s composition. The post-translational import mechanism means biogenesis is a two-part process: first the vesicle is formed, and second, it is equipped with the proteins required for its metabolic roles.
Molecular Machinery of Protein Import (Peroxins)
The transport of proteins into the peroxisome is carried out by proteins called peroxins, encoded by PEX genes. This machinery works in a cycle to recognize, dock, and move cargo into the organelle. The process begins in the cytosol, where receptor proteins identify the targeting signals on peroxisomal proteins. The peroxin PEX5 is the primary receptor for the PTS1 signal, while PEX7 recognizes the PTS2 signal.
Once the peroxin receptor binds its cargo, the complex travels to the peroxisome and attaches to its surface. This docking step is mediated by a platform of peroxins, including PEX13 and PEX14, embedded in the membrane. These proteins anchor the receptor-cargo complex, positioning it for translocation and ensuring only appropriate cargo is delivered.
Following docking, the cargo is moved into the peroxisomal matrix. This translocation is facilitated by other peroxins, including PEX2, PEX10, and PEX12, which form the RING finger complex. This complex creates a transient pore that allows the folded protein to pass through the membrane. Peroxisomes can import fully folded proteins and even multi-protein complexes.
After the cargo is released inside the peroxisome, the receptor is recycled back to the cytosol. This active process requires energy in the form of ATP. Two peroxins, PEX1 and PEX6, are ATPases that use this energy to extract the PEX5 receptor from the membrane, making it available for another round of import.
Clinical Relevance of Biogenesis Defects
Failures in peroxisome biogenesis lead to severe, inherited metabolic conditions known as Peroxisome Biogenesis Disorders (PBDs). These diseases arise from mutations in the PEX genes, which encode the peroxin proteins. When a peroxin is non-functional, the import of enzymes into the peroxisome is impaired. This results in peroxisomes that are structurally present but metabolically inert, often called “ghost” peroxisomes because they are empty of their matrix proteins.
The most severe form of PBD is the Zellweger syndrome spectrum (ZSS), a continuum of disorders with varying severity. These include the most severe Zellweger syndrome, neonatal adrenoleukodystrophy, and the mildest form, infantile Refsum disease. Clinical outcomes are tied to the specific PEX gene mutation and its impact on peroxin function. A mutation that completely abolishes a peroxin’s function leads to a more severe presentation than one that only partially impairs it.
The consequences of these defects are systemic, affecting multiple organ systems. The accumulation of very long-chain fatty acids disrupts nerve cell function, causing severe neurological problems. A failure to synthesize plasmalogens further contributes to issues in the heart and brain. Patients with ZSS present with symptoms including liver dysfunction, kidney abnormalities, and distinctive facial features, underscoring the importance of functional peroxisomes.