Lysosomal Physiology

Abstract

Lysosomes are acidic compartments filled with more than 60 different types of hydrolases. They mediate the degradation of extracellular particles from endocytosis and of intracellular components from autophagy. The digested products are transported out of the lysosome via specific catabolite exporters or via vesicular membrane trafficking. Lysosomes also contain more than 50 membrane proteins and are equipped with the machinery to sense nutrient availability, which determines the distribution, number, size, and activity of lysosomes to control the specificity of cargo flux and timing (the initiation and termination) of degradation. Defects in degradation, export, or trafficking result in lysosomal dysfunction and lysosomal storage diseases (LSDs). Lysosomal channels and transporters mediate ion flux across perimeter membranes to regulate lysosomal ion homeostasis, membrane potential, catabolite export, membrane trafficking, and nutrient sensing. Dysregulation of lysosomal channels underlies the pathogenesis of many LSDs and possibly that of metabolic and common neurodegenerative diseases.

The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

“…Acidic lysosomal organelles mediate crucial biological processes such as degradation, catabolite export, and metabolism-sensing 5–7 , and defects to these processes can result in lysosomal storage diseases 8–10 . The lysosomal membrane is decorated with channels and transporters that regulate the lysosome’s ionic homeostasis and physiological functions 5,11,12 .…”

“…The lysosomal membrane is decorated with channels and transporters that regulate the lysosome’s ionic homeostasis and physiological functions 5,11,12 . Recently, a previously uncharacterized transmembrane protein 175 (TMEM175) was identified as the bona fide endo/lysosomal K + channel, whose function is important for setting the lysosomal membrane potential and maintaining pH stability 1 .…”

Lysosomes in programmed cell death pathways: from initiators to amplifiers

“…Lysosomes are ubiquitous sphere or tubular shape organelles. Their size, abundance and distribution are dependent on the digestive activity and cell type (Xu and Ren, 2015). Lysosomal membrane, which was long thought to serve primarily as the physical barrier to prevent mixing of the highly acidic lumen with cytosol, is known to have a number of other important functions, which are largely associated with the numerous membrane proteins transporters, receptors and enzymes, anchored into the lysosomal membrane.…”

“…During endocytosis the substrates are first enclosed into the early endosomes, which mature into the late endosomes that finally fuse with lysosomes, resulting in digestion of the engulfed material. However, endocytosis is not only related to degradation by lysosomes, but it is also implicated into recycling of surface receptors and cellular signalling (Sigismund et al, 2012;Settembre et al, 2013;Xu and Ren, 2015). During autophagy, the engulfed contents are transported from the cytoplasm to the lysosomes for final degradation (Ciechanover, 2012;Kaur and Debnath, 2015).…”

“…The acidic pH is maintained by V-ATPase and ion homeostasis that are essential for lysosomal maturation and trafficking, proper membrane fission and establishment of the lysosomal membrane potential (Xu and Ren, 2015).…”