Whole-Cell Scale Dynamic Organization of Lysosomes Revealed by Spatial Statistical Analysis

Abstract

SUMMARY In eukaryotic cells, lysosomes are distributed in the cytoplasm as individual membrane-bound compartments to degrade macromolecules and to control cellular metabolism. A fundamental yet unanswered question is whether and, if so, how individual lysosomes are organized spatially to coordinate and integrate their functions. To address this question, we analyzed their collective behavior in cultured cells using spatial statistical techniques. We found that in single cells, lysosomes maintain non-random, stable, yet distinct spatial distributions mediated by the cytoskeleton, the endoplasmic reticulum (ER), and lysosomal biogenesis. Throughout the intracellular space, lysosomes form dynamic clusters that significantly increase their interactions with endosomes. Cluster formation is associated with local increases in ER spatial density but does not depend on fusion with endosomes or spatial exclusion by mitochondria. Taken together, our findings reveal whole-cell scale spatial organization of lysosomes and provide insights into how organelle interactions are mediated and regulated across the entire intracellular space.

Asymptotic Behavior of the Solution of the Space Dependent Variable Order Fractional Diffusion Equation: Ultraslow Anomalous Aggregation

“…The majority of these organelles are concentrated in the perinuclear area. A fundamental unresolved question is how lysosomes are self-organized spatially to coordinate their roles [24]. In this Letter, we propose a new anomalous mechanism by which nonuniform distribution of subdiffusing organelles can occur.A generic model for anomalous diffusion in inhomogeneous media is the space-dependent variable-order fractional diffusion equation [12][13][14][15][16] ∂p(x, t) ∂twhere p(x, t) is the probability density function (PDF) of a particle at position x and time t. This function can be also interpreted as the mean number density of subdiffusive particles.…”

Endosome motility defects revealed at super-resolution in live cells using HIDE probes

“…SIM has been used to image endosomes for over 3 minutes, but the resolution possible with this technique (> 100 nm) 9 is insufficient to reliably differentiate individual endosomes. Quantifying endosome dynamics is even more challenging, as doing so requires the combination of high temporal resolution (> 1 frame/sec) 10 , deep cell penetration to visualize the critical perinuclear region 11 , and high spatial resolution to differentiate individual endosomes from within a densely packed array 6 . While each of these essential elements has been demonstrated individually to varying degrees of success 6 , 10 , 11 , all three are needed simultaneously to capture and rigorously quantify endosome motility and understand its connection to normal cell function and disease.…”

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

“…Lysosomes move within a cell in a regulated manner (reviewed recently in Ba et al, 2018;Pu et al, 2016). Their motility leads to the formation of distinct lysosome populations that differ in intraluminal pH and degradative activities (Bright et al, 2016;Johnson et al, 2016).…”