Lysosomal size matters

Abstract

Lysosomes are key cellular catabolic centers that also perform fundamental metabolic, signaling and quality control functions. Lysosomes are not static and they respond dynamically to intra- and extracellular stimuli triggering changes in organelle numbers, size and position. Such physical changes have a strong impact on lysosomal activity ultimately influencing cellular homeostasis. In this review, we summarize the current knowledge on lysosomal size regulation, on its physiological role(s) and association to several disease conditions.

Keywords: AMPK; BORC; LAMTOR; PIKfyve; PtdIns(3)P; PtdIns(3,5)P2; PtdIns(4,5)P2; V-ATPase; autolysosome; autophagy; endolysosome; fission; fusion; late endosome; lysosomal acidification; lysosomal reformation; lysosomal storage disorders; lysosome.

Figure 1

Electron micrographs of snap‐frozen lysosomes displaying general morphology and size variations of the almost spherical organelles in HT1080 human fibrosarcoma cells. The term lysosome is used in a broad sense comprising both terminal lysosomes resulting from cargo endocytosis as well as autolysosomes. Those organelles are characterized by an opaque matrix, containing frequently more or less degraded (membrane) material and/or a completely electron‐dense core. A, Under wildtype conditions the lysosomal diameter (white arrow) is on average 400 nm. B, After deletion of BLOC‐1 related complex (BORC) the mean diameter decreases to approximately 300 nm; m = mitochondrion; scale bar = 400 nm

Figure 2

Comprehensive scheme of key components and protein machineries of late endosomes/lysosomes/autophagosomes and their involvement in the regulation of organelle size. For the purpose of graphical simplification in this figure, the term lysosome refers to endolysosomes, terminal lysosomes and autolysosomes. The image has been subdivided into different boxes annotated with red letters, A‐E, so as to link the machineries to the respective text paragraphs. The localization of PIP(3,5)P₂ to lysosomal reformation tubules, as postulated by References 27, 30 is still hypothetical; this is indicated by the use of a dashed line in pink and gray for this feature

Figure 3

Model summarizing the working hypotheses underlying LSD pathophysiology. Under healthy conditions (left part of the scheme), correct acidification, fusion and fission events maintain the organelle's function and morphology. In contrast, LSD display alterations of the regulatory mechanisms controlling the organelle's size (right part of the scheme), either as an impairment of autophagosome‐lysosome fusion (highlighted in green, I) and/or as a reduction of lysosomal reformation (highlighted in green, II) that subsequently lead to the accumulation of autophagic compartments and enlarged endolysosomes. These alterations are accompanied by acidification (blue color gradient) defects that promote the accumulation of undegradable cargo in catabolically inactive organelles. Finally, these events are amplified in a feedforward loop that culminates in the progressive phenotype characteristic of LSD