LYSOSOMES
LYSOSOMES
LYSOSOMES
www.journalofscience.net
ABSTRACT
Lysosomes are vigorous organelles that receive and degrade macromolecules from the secretory, endocytic,
autophagic and phagocytic membrane-trafficking pathways. Live-cell imaging has shown that fusion with lysosomes occurs
by both transient and full fusion events, and yeast genetics and mammalian cell-free systems have identified much of the
protein machinery that coordinates these fusion events. Many pathogens that hijack the endocytic pathways to enter cells
have evolved mechanisms to avoid being degraded by the lysosome. However, the function of lysosomes is not restricted to
protein degradation: they also fuse with the plasma membrane during cell injury, as well as having more specialized secretory
functions in some cell types.
INTRODUCTION
Interest in lysosomes and lysosomal enzymes cell surface receptor binding exogenous lysosomal
was stimulated by the existence of some 30 inherited enzymes and mediating their transfer to lysosomes along
lysosomal storage disorders in man. The enzyme defects the pathway of receptor-mediated endocytosis. We now
involved in most of these disorders were identified in the know that this receptor functions also in transport of
1970s; see review by Neufeld, Lim, & Shapiro in this endogenous lysosomal enzymes and that its presence in
series in 1975. Presently, these mutations are being organelles that constitute elements of the secretory
characterized at the level of DNA and RNA. Targeting of pathway is important for that function. The combined
lysosomal enzymes is part of the more general question: application of biochemical and cytological methods has
how do eukaryotic cells transport proteins synthesized in significantly contributed to the present knowledge of
the rough endoplasmic reticulum to diverse destinations? lysosomal enzyme transport [4, 5].
Hickman & Neufeld discovered, in 1972, that the multiple Lysosomes are organelles in which cellular
deficiency of lysosomal enzymes in I-cell disease results degradation occurs in a controlled manner, separated from
from a deficiency in a recognition marker that is common other cellular components. As several pathways terminate
to lysosomal enzymes and required for targeting the in the lysosome, lysosomal dysfunction has a profound
enzymes to lysosomes. This observation provided the impact on cell homeostasis, resulting in manifold
basis for many subsequent studies that eventually led to pathological situations, including infectious diseases,
the identification of the recognition marker and its neurodegeneration, and aging. Lysosomal biology
receptor [1-3]. A 2 15-kd receptor, which recognizes demonstrates that in addition to regulating the final steps
mannose 6-phosphate residues in lysosomal enzymes, has of catabolic processes, lysosomes are essential up-stream
been identified as an essential component of a system that modulators of autophagy and other essential lysosomal
in many cells allows for specific transport of lysosomal pathways. Lysosomal membrane permeabilization offers
enzymes to lysosomes. It was originally identified as a therapeutic potential in the treatment of cancer, though
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the molecular regulators of this process remain obscure. morphological criteria. Biochemical or cytochemical
demonstration of acid hydrolase activity was required. By
Basics of Lysosome 1962, the number of hydrolytic enzymes identified had
The history of most cell organelles has been increased to 10. It was apparent that while most of these
early description by microscopists followed many years were present in all lysosomes, their proportions probably
later by isolation and biochemical characterization. The varied considerably from tissue to tissue [11-14].
lysosome is an exception in that it originated as a
biochemical concept and morphological identification Membrane traffic routes to lysosomes
followed. Among investigators isolating mitochondria and Considerable information is now available concerning
microsomes by differential centrifugation of cell how newly synthesized hydrolases and membrane
homogenates, there was some disagreement as to which proteins are delivered from the trans-Golgi network
fraction contained the enzyme acid phosphatase. Some (TGN) to lysosomes in mammalian cells. Many of the
found it in the mitochondrial while others, using proteins in the mammalian trafficking machinery are
somewhat lower centrifugal force, found it in their orthologues of those used by Saccharomyces
microsome fraction [6]. This problem was resolved by cerevisiaefor delivery from the Golgi to the vacuole (the
DeDuve and his associates, who were able to separate the yeast equivalent of the mammalian lysosome) [15-16].
classical mitochondrial fraction into two subfractions. The
lighter (L) fraction consisted of particles rich in acid Lysosomal Function: New Insights
phosphatase but lacking the mitochondrial enzyme Several recent findings have demonstrated the
cytochrome oxidase. These particles, which also central role of the lysosome in controlling cellular
contained cathepsin, ribonuclease, deoxyribonuclease, responses to nutrients. Mammalian target of rapamycin
and 3-glucuronidase, were recognized as a new particulate complex 1 (mTORC1) is a kinase that regulates the
component of cells distinct from mitochondria and were cellular response to amino acids, growth factors, and
given the name lysosomes to draw attention to their energy levels within the cell. mTORC1translocates to the
richness in hydrolytic enzymes. Another defining lysosomal membrane in the presence of amino acids. This
characteristic of lysosomes was the fact that they were translocation is regulated by a multiprotein complex
impermeable to their substrates and were enzymatically named Ragulator, which serves as an aminoacid-regulated
active in vitro only after disruption or treatment with a docking site for mTORC1 on lysosomal membranes
surface active agent. It was thus inferred that they must be [17,18]. At this location mTORC1 phosphorylates
enclosed by a membrane-like barrier. When centrifugal downstream effectors that modulate cell metabolism and
pellets of fractions enriched in lysosomes were examined block autophagy.Arecent study by Narita et al. further
in thin sections with the electron microscope, a high linked lysosomes and mTORC1, demonstrating that
proportion of the granules were obviously different from lysosomes spatially link mTOR and autophagy in a
mitochondria. They had a dense heterogeneous content compartment known as TOR-autophagy spatial coupling
and, as postulated, they were enclosed by a membrane. compartment during Ras-induced senescence.
Fortunately a dependable cytochemical method was
available for the lysosomal enzyme acid phosphatase [7- Lysosomes in Cancer Therapy
10]. Cytochemical observations at the light and electron The capacity of lysosomes to kill cells through
microscope level confirmed that the acid phosphatase of LMP has been exploited in the development of cancer
liver was not localized in mitochondria but in membrane- treatments. A wide variety of agents can kill cancer cells
bounded dense bodies in the vicinity of the bile canaliculi. in vitro. To develop efficient and nontoxic cancer
Unlike mitochondria and other cell organelles which have therapies, a distinction must be made between healthy and
a consistent, clearly defined and easily recognizable tumor cells, since all cells contain lysosomes. However,
structure, the granules exhibiting acid phosphatase lysosomes from cancer cells exhibit several properties
activity varied in size and were highly heterogeneous in that differ from those of un-transformed cells, which may
their internal structure. Some were spherical with a be exploited in therapeutic strategies. During cellular
uniform content of moderate density; others were transformation, cancer cells undergo profound lysosomal
irregular in outline and contained aggregations of very changes, affecting size, intracellular localization,
dense granules in a less dense matrix. Others contained cathepsin expression, and enzymatic activity. Moreover,
myelin figures or crystalline inclusions. It was this several findings suggest that lysosomes from cancer cells
extraordinary pleomorphism that had prevented may be more susceptible to LMP. For example, the
cytologists from recognizing lysosomes as a distinct increased size of lysosomes in cancer cells renders them
entity. This was the first instance of an organelle that more susceptible to destabilizing agents [19-22].
could not be identified with confidence solely by
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