Lysosomes: Function, Pathology, and Clinical Significance
Digestion and Product Reuse: The majority of substances digested by lysosomes (heterolysosomes, autolysosomes, secondary lysosomes) are reused. Through membrane porins, they enter the hyaloplasm where they are utilized. Excretion: Undigested material remaining in lysosomes can be removed from the cell via exocytosis (cellular microdefecation). However, sometimes the cell cannot remove this material, retaining it until cell death. Residual Bodies: A residual body is a heterolysosome vacuole, or a lysosome, containing undigested residues. Depending on the residue, myelin figures may form due to alterations in phospholipoprotein degradation. The protein fraction is completely digested, while the lipid fraction is only partially digested. Myelin-like figures consist of parallel monolayers, often arranged in spirals or concentric lamellae. Lipofuscin: This is a brown age pigment resulting from the enzymatic oxidation of lipids.
Pathobiology: Lysosomal pathology can be congenital (membrane, content, or function impairment) or acquired (membrane, content, or function alteration). Congenital: Chediak-Higashi Syndrome: Certain genes responsible for lysosomal membrane synthesis are affected. Lysosomal enzyme content is abnormal, and lysosomes tend to fuse, forming giant lysosomes with irregular contours. Type I Cell Disease: Lysosomes lack proteins necessary for organelle recognition. Instead of going to endosomes, they are directed to the membrane. Lysosomal Storage Diseases (Tesaurismosis): The absence of one or more enzymes causes product accumulation within lysosomes. Sometimes, this leads to the accumulation of products not normally produced by the cell (e.g., Pompe disease). Clinical manifestations include a systolic murmur at birth, with death often occurring in the first year. Cardiomegaly, hypotonia, muscular hypertrophy, and macroglossia are observed. Many such diseases exist (approximately 30), including Niemann-Pick, Gaucher, Tay-Sachs, Fabry, and Hurler diseases. Acquired: Pneumoconiosis: A lung disease caused by inhaling coal dust, silica, beryllium, tin, or zinc. Lung lesions cause dyspnea. Inflammatory reactions damage the bronchi and cause lung parenchyma sclerosis. Silicosis is the most significant form. Crystalline silica is phagocytosed by alveolar macrophages; lacking enzymes to destroy it, silica accumulates. Cellular debris is phagocytosed by new macrophages, leading to fibrosis and lung failure. Gout: Similar to pneumoconiosis, but with uric acid crystals in joints. Altered Function: Microorganisms can alter lysosomal function. Some lyse endocytic vacuole walls (trypanosomiasis), others inhibit lysosome fusion (tuberculosis), some destroy the capsule surrounding released pathogens (some viruses), and others lyse the lysosomal membrane (streptococci).
Lysosomal Enzyme Synthesis: Lysosomal enzymes are synthesized in the ER with a signal peptide. After signal peptide removal, N-glycosylation occurs. In the cis-Golgi, the oligosaccharide chain is modified by N-acetylglucosamine and N-acetyl glucosaminidase, losing some mannose residues. Two terminal mannose residues are phosphorylated, serving as a marker. The trans-Golgi has receptors for mannose-6-phosphate (M6P), binding the enzymes to the membrane. Vesicles coated with clathrin/adaptin bud off, forming primary lysosomes or prelysosomes.
Heterophagy: Heterophagy is the degradation of materials taken up by the cell via phagocytosis or endocytosis. Phagosomes: Vacuoles formed by phagocytosis (macrophages or leukocytes engulfing foreign bodies, necrotic cell fragments, or microorganisms). Proteins like MARCKS, PKC, and myosin I are involved in phagosome formation and maturation. Phagosomes fuse with prelysosomes or primary lysosomes, forming phagolysosomes or heterophagolysosomes. Endocytic vacuoles lose their clathrin coat and fuse with early endosomes, recycling receptors to the plasma membrane. Heterophagy functions include: Defense: Leukocytes and macrophages destroy microorganisms and cellular debris. Cellular Turnover: Old or defective cells (e.g., red blood cells) are phagocytosed. Protein Reabsorption: Proteins (e.g., albumin) are recovered by renal tubular cells. Glycoprotein Catabolism: Altered glycoproteins are removed from circulation. Cholesterol Metabolism: LDL is taken up, and cholesterol is released. Thyroid Hormone Secretion: Thyroid follicular cells phagocytose thyroglobulin fragments, releasing T3 and T4. Hormone Processing: Peptide hormones are degraded. Photoreceptor Renewal: Photoreceptor discs are phagocytosed and processed.