Peroxisomes: Structure, Function, and Associated Diseases
Peroxisomes. In 1954, Rhodin found small organelles in the proximal tubule of mouse kidneys, which he called “microbodies.” In 1962, Novikoff discovered microperoxisomes. These self-replicating organelles, bound by a single membrane, are present in all eukaryotic cells. They contain enzymes and are involved in:
- Control of lipid homeostasis by beta-oxidation
- Conversion of cholesterol into bile salts (liver only)
- Plasmalogen biosynthesis
- Cellular respiration
- In plants, seed peroxisomes convert fatty acids into carbohydrates via the glyoxylate cycle.
Morphology and Composition Peroxisome number varies by cell type; they are most abundant in the liver and kidneys. In the liver, they are involved in cholesterol metabolism and gluconeogenesis. These ovoid organelles range from 0.15 to 1.7 μm in diameter. They are bound by a peroxisomal membrane and contain a homogeneous matrix, a nucleoid, and a marginal plate. The peroxisomal membrane has a tripartite structure. The matrix is moderately electron-dense. The marginal plate is flat, linear, 8.5 nm thick, homogeneous, dense, and separated from the peroxisome membrane. Peroxisomes are arranged in a network of fine tubules. Canaliculi and peroxisomes share functions. In humans, peroxisomes rarely show a homogeneous matrix and marginal plaques. The peroxisome membrane is 30% lipid and 70% protein. It contains electron carriers (cytochrome P-450, cytochrome b), enzymes involved in lipid metabolism, oxidoreductases, and peroxin.
Biogenesis Peroxisomes are formed from pre-existing peroxisomes. PEX genes are responsible for peroxisome assembly and maintenance, encoding all matrix and membrane proteins. PEX genes are controlled by peroxisomal proliferators. Peroxins act as shuttles between the cytosol and the peroxisomal membrane, complexed with proteins carrying PTS1 or PTS2 signals in the cytosol. Peroxisomal biogenesis is associated with cell proliferation.
Role
Catabolism:
- Degradation of purines
- Participation in fatty acid beta-oxidation
- Degradation of alcohol
- Degradation of cholesterol derivatives
Anabolism:
- Biosynthesis of lipid esters (plasmalogens)
- Gluconeogenesis
- Short-chain fatty acid oxidation
Pathobiology Seventeen human peroxisomal genetic diseases have been described; fifteen affect the nervous system. These recessive lethal diseases result from mutations in genes encoding peroxisomal enzymes. They are childhood diseases, often lethal within the first ten years of life, affecting fewer than one in 50,000 newborns.
Diseases of Group A: Characterized by the absence of multiple peroxisomal enzymes.
- Zelweger Syndrome: Craniofacial dysmorphism, bilateral cataracts, retinopathy, liver disease, small renal cysts, and cerebral hypomyelination.
- Neonatal Adrenoleukodystrophy: X-linked genetic disease caused by acyl-CoA oxidase deficiency. Severe forms affect the CNS; adrenal insufficiency may be the sole manifestation. Very long-chain fatty acid accumulation occurs due to absent peroxisomal beta-oxidation.
- Refsum disease
- Hyperpipecolic acidemia
Diseases of Group B:
- Rhizomelic Chondrodysplasia Punctata: Rhizomelic dwarfism, cataracts, calcification, and ichthyosis.
Diseases of Group C: Includes adrenoleukodystrophy and diseases caused by single peroxisomal enzyme deficiencies.
- Adrenoleukodystrophy: X-linked; characterized by very long-chain fatty acid accumulation in white matter, adrenal glands, fibroblasts, and blood plasma due to VLCFA-CoA deficiency. Affects 1 in 15,000 males. Neurological symptoms result from cerebral demyelination and peripheral nerve and spinal cord impairment.
- Refsum Disease: Caused by dihydroxyacetone phosphate acyltransferase deficiency; affects the CNS and peripheral nervous system.
- Hyperoxaluria: Due to peroxisomal AGT (alanine glyoxylate aminotransferase) gene mutation. Glyoxylate oxidation to oxalate leads to insoluble calcium oxalate, causing kidney stones (nephrocalcinosis).