© 1999 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999

8.5.3.8 Lysosomes and Proteasomes

Lysosomes are Golgi-budded organelles that contain ~40 digestive enzymes⁵³¹ capable of degrading all major classes of biological macromolecules -- including at least 5 phosphatases, 4 proteases, 2 nucleases, 6 lipases, 12 glycosidases, and an arylsulfatase.⁹³⁹ These enzymes are needed both to degrade materials brought into the cell from the outside and to degrade internal cellular structures that are damaged or are no longer needed. Lysosomal enzymes are acid hydrolases stored inside the lysosome as small granules 5-8 nm in diameter -- protein aggregates of the hydrolytic enzymes with a pH optimum around 5, representing over 60% of organelle mass.⁵³¹ The lysosomes can release these enzymes after fusion with endosomes containing foreign matter, or to digest dead portions of the cell or malfunctioning organelles, or to destroy abnormal substances such as bacteria that enter the cell. An unusual oligosaccharide containing mannose-6-phosphate (M6P) serves as a recognition marker or address that targets all such enzymatic proteins to the lysosomes, and sorting nexins are proteins containing lysosomal targeting codes using either tyrosine or dileucine-based motifs.¹⁰³² These membrane markers are readily detectable by nanorobots suitably equipped with transmembrane sensory tools, although it is important not to destroy the membrane integrity or to allow leaks (Section 9.4.5.5) which may alter fluid pH, during any probing. Since intralysosomal pH is different from the rest of the cell, chemosensors intended to probe the lysosomal interior may require a different design (or different detection parameters) than cytosolic chemosensors. In general, nanorobots can exploit the same biochemical markers that the cell normally uses to transport organelles to specific locations within the cell. Organelle surface chemosensing is most valuable for navigation and identification, while chemosensing of the organelle interior is also important for diagnosis and treatment (Chapter 21).

Lysosomes are spherical or nearly spherical organelles, typically 0.5-1 microns (range 50 nm to 3 microns) in diameter. They vary greatly in appearance and content according to cell type and also in relation to the physiological state of a particular cell. The lysosome has a unique 5-6 nm three-layered membrane⁹³⁸ with a special transmembrane transport protein that uses ATP to pump H⁺ into the organelle lumen, thereby maintaining the internal pH at 5. The lysosomal membrane also has special docking marker acceptor proteins that mark a lysosome as a target for fusion with specific transport vesicles in the cell. Soluble products of digestion can cross the membrane, exit the organelle, and enter the cytosol for recycling into the cellular metabolism. Indigestible material slowly accumulates in the cytoplasm as lipofuscin pigment granules and other residual bodies. Lysosomes are present in most cells except red cells.

Although it is normally quite stable, the lysosome membrane can become more fragile when the cell is injured or deprived of oxygen or when excessive amounts of vitamin A are present. Lysosomes were once called "suicide sacs" because lysosomal rupture can result in self-digestion of the cell, a process known as autolysis. However, it is now known that lysosomes are part of the normal cellular digestion apparatus relating the process of endocytosis to the processes of intracellular synthesis, storage, and transport,⁹³⁸ and structural deterioration of lysosomes does not occur rapidly in ischemic or postmortem cells.^2019,2020 Most of the digestive enzymes require the low pH of the lysosomal or peroxisomal vesicles for activation (just as some proteases require the low pH of the stomach).

In addition to the lysosomal degradation system, there is also a large number of small cytosolic proteasomes (each having a 700,000-dalton 20S core complex ~11 nm in diameter). This serves as an extralysosomal ATP-driven system for selectively degrading endogenous ubiquitinated proteins in virtually all human cells^{1087,1088,3383} (Chapter 13). Indeed, the ~2 megadalton 26S proteasome complex (containing 30-40 different proteins) appears to be the major protease of the nuclear and cytoplasmic compartments of the eukaryotic cell -- proteasomal degradation controls the lifetime of most cellular proteins, including many regulatory proteins, and generates peptide antigens for presentation by MHC Class I molecules to CD8⁺ cytotoxic T cells.²⁹¹⁵ Proteasomes are ubiquitous and very abundant, comprising up to 1% of total cellular protein.^{1087,2916,2917} The entire 26S complex is 30-44 nm in length.

Last updated on 20 February 2003