Damage Mediated by Dysfunction of Organelles and Cellular Systems: Lysosomes

Abstract

Lysosomes were discovered more than five decades ago and characterized as cytoplasmic organelles loaded with acid hydrolases responsible for the digestion of macromolecules and cellular debris. The membrane bilayer surrounding the lysosomes not only limits the nonspecific diffusion of the molecular digestive machinery to the cytosol but also ensures the acid pH required for the activity of acid hydrolases. This specialized digestive function is critical in the maintenance of cellular homeostasis and energy metabolism by clearing wasted constituents and damaged organelles. Besides these critical functions, lysosomes participate in apoptotic pathways due to the permeabilization of the lysosomal membrane and subsequent release of cathepsins, which recruit mitochondria to execute cell death, and are key regulators of autophagy. Alterations in lysosomal composition due to the accumulation of metabolites and lipids can have a broad impact in cellular homeostasis by modulating the fusion of autophagosomes with lysosomes for final cargo disposition. Accumulation of lipid intermediates in lysosomes is thought to contribute to the disruption in cellular homeostasis and metabolism, underlying the widespread pathological manifestations of many lysosomal storage diseases (LSDs). Thus, a better understanding of the biology of lysosomes may be of relevance in cellular physiology and in the treatment of LSDs