The Biology of Lysosomes: From Order to Disorder

Abstract

Since its discovery in 1955, the understanding of the lysosome has continuously increased. Once considered a mere waste removal system, the lysosome is now recognised as a highly crucial cellular component for signalling and energy metabolism. This notable evolution raises the need for a summarized review of the lysosome’s biology. As such, throughout this article, we will be compiling the current knowledge regarding the lysosome’s biogenesis and functions. The comprehension of this organelle’s inner mechanisms is crucial to perceive how its impairment can give rise to lysosomal disease (LD). In this review, we highlight some examples of LD fine-tuned mechanisms that are already established, as well as others, which are still under investigation. Even though the understanding of the lysosome and its pathologies has expanded through the years, some of its intrinsic molecular aspects remain unknown. In order to illustrate the complexity of the lysosomal diseases we provide a few examples that have challenged the established single gene—single genetic disorder model. As such, we believe there is a strong need for further investigation of the exact abnormalities in the pathological pathways in lysosomal disease.

A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

“…Lysosomal damage serves as both a cause and consequence of many disease conditions, including infectious and neurodegenerative diseases(Amaral et al, 2023; Ballabio et al, 2020; Bonam et al, 2019; Fehrenbacher et al, 2005). We tested whether the above molecular and cellular processes that transduce lysosomal damage signals to induce SG formation are important for cell survival in disease contexts.…”

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These agents, along with various others, damage lysosomes, leading to the leakage of acidic contents and the disruption of cellular functions, thereby threatening cell survival (Patra et al, 2023;Saftig et al, 2021; Fengjuan Wang et al, 2018). Lysosomal damage is strongly linked to various human diseases, e.g., cancer, infectious, and neurodegenerative diseases (Amaral et al, 2023;Ballabio et al, 2020;Bonam et al, 2019;Fehrenbacher et al, 2005). Although lysosomal damage is of physiological importance and pathological relevance, understanding of how cells respond to this damage remains largely unknown (C. Papadopoulos et al, 2017).Cells can detect lysosomal damage through several mechanisms, including the identification of calcium leakage or the exposure of luminal glycan (Aits et al, 2015;Radulovic et al, 2018;Skowyra et al, 2018).

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Cholesterol Metabolite 27-Hydroxycholesterol Enhances the Secretion of Cancer Promoting Extracellular Vesicles by a Mitochondrial ROS-Induced Impairment of Lysosomal Function

“…Interestingly, there have been several reports that an increase in MVB size can result from decreased trafficking of MVBs towards the lysosome (13,43). Lysosomes are a crucial regulatory component of the cell and is involved in maintaining cellular homeostasis by actively degrading and recycling intracellular components and is also involved in regulating cellular signaling and metabolism (44,45). Lysosomes act as the fate determining step for MVBs once they are formed-MVBs can either fuse with the lysosome and get degraded, where the cargo gets recycled within the cell, or the MVBs can fuse with the plasma membrane and release its contents as EVs (46).…”

Golgi defect as a major contributor to lysosomal dysfunction

“…A defining feature of lysosomes is their ability to maintain an acidic pH of around 4.5, a critical condition for the optimal activity of hydrolytic enzymes ( Amaral et al, 2023 ). These organelles contain numerous hydrolases that can break down various biomolecules, including proteins, lipids, carbohydrates, nucleic acids, misfolded or damaged proteins and organelles, and cellular debris.…”

“…Lysosomes are membrane-bound organelles that contain various hydrolytic enzymes that break down different types of biomolecules. Lysosomes are known for their high dynamics, capable of fusing with membrane vesicles originating from endocytosis, autophagocytosis, and phagocytosis ( Bajaj et al, 2019 ; Amaral et al, 2023 ). Lysosomes play a crucial role in cellular waste disposal, digestion of foreign materials, recycling of cellular components, and signaling.…”