Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

Abstract

Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.

Genome-wide expression analysis in a Fabry disease human podocyte cell line

“…α-gal A deficiency results in the progressive and systemic accumulation of globotriaosylceramide (Gb 3 or GL-3) and other related glycosphingolipids in lysosomes [ 3 ]. The emergence of new multifaceted roles of the lysosome in several cellular processes and its primary function of macromolecule degradation sheds light on the mechanisms underlying FD and LDs in general [ 4 ]. Thus, lysosomes participate in vital processes such as antigen presentation, cell adhesion, apoptotic cell death, interorganellar communication, and gene regulation [ 5 ].…”