Lysosomal storage diseases, including lysosomal acid lipase deficiency, were first described in the 19th century, even before lysosomes were clearly defined in biology. They were initially characterized as a group of symptoms—as opposed to the molecular diagnosis we use today. 

“Knowledge on lysosomal storage diseases has been evolving for more than a century,” Parenti and colleagues wrote in the opening paragraph of their study on lysosomal storage diseases published in EMBO Molecular Medicine. 

In the mid-20th century, our understanding of lysosomes accelerated. Scientists began to uncover the ways in which lysosomal enzymes functioned, and developed tools to better understand them from a molecular basis. Enzyme replacement therapy, the current mainstay treatment of lysosomal storage diseases, was introduced in the 1990s. 

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Foundational Concepts of Lysosomes

Early on, scientists understood the primary function of lysosomes to be the turnover of cellular constituents. Lysosomes play a major role in the degradation of a number of important compounds, including proteins, glycogen, and nucleic acids. These materials reach the lysosomes through a variety of routes. Scientists understood lysosomal degradation as being vital for cellular homeostasis. 

In the late 1970s and 1990s, researchers made progress in understanding how lysosomal biology plays out in the pathophysiology of lysosomal storage disorders. Scientists were able to characterize the mechanisms underlying the sorting of lysosomal enzymes and identify the molecular bases for lysosomal storage disease variability. 

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Studies have revealed that there are more than 200 lysosomal-resident proteins that contribute to the function of lysosomes. Around a quarter of these are acidic hydrolases, most of them acting as exoglycosidases or sulfatases. 

These proteins are either localized to the lysosomal lumen or the membrane. Their functions are diverse: creating a glycocalyx-like layer, facilitating transportation across the membrane, ensuring membrane stability, and mediating interactions with other cellular structures. 

Current Views of Lysosomes 

“Recent discoveries have changed the former consideration of lysosomes as organelles that degrade and recycle cellular waste,” Zhang and colleagues wrote in the Journal of Hematology & Oncology. “It is now clear that lysosomes are key organelles in degradation, innate and adaptive immunity, and nutrient sensing.” 

Lysosomal degradation can be classified as endocytosis and autophagy. This process is so vital that autophagy dysfunction has been pointed to as the cause of many lysosomal storage disorders. Today, medical researchers are investigating new ways to target autophagy dysfunction as a therapeutic intervention. 

The immune function of lysosomes has also been clarified in recent years. We now understand that immunity is directly affected by lysosomal activity in macrophages and dendritic cells. Pathogens like bacteria undergo phagocytosis and are sent to lysosomes for degradation. Should bacteria escape into the cytosol, autophagy represents an additional mechanism that captures bacteria and directs it to be degraded via lysosomal activity. 

The nutrient-sensing function of lysosomes has garnered widespread attention among the medical research community in recent years. Not only are lysosomes able to monitor the nutrient status of cells, they are also able to adjust their metabolism according to shifting energy needs. 

“Lysosomes function as platforms for metabolic signal transduction and for detecting variations on the levels of different nutrients, including amino acids, glucose and lipids, in particular cholesterol,” Saftig and Puertollano wrote in Trends in Biochemical Sciences. 

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Mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism. It promotes a number of important anabolic processes, such as protein synthesis, glucose metabolism, and the biosynthesis of nucleotides and lipids. When amino acid levels fall below a threshold level, Ras-related GTP-binding protein (Rag) shuttles mTORC1 to the cytosol, terminating the signaling of mTORC1 under starvation conditions. 

AMP-activated protein kinase (AMPK) is a critical energy sensor and metabolism regulator. Activated AMPK causes the phosphorylation of downstream targets to ultimately restore deficient ATP levels. Under high glucose conditions, AMPK remains inactive; in glucose starvation conditions, AMPK is activated. Both these processes are mediated by lysosomes. 

Lysosomes also play an important role in cholesterol homeostasis. Lysosomal dysfunction has been implicated in triggering the pathological changes that result in atherosclerosis via regulatory autophagy, apoptosis, inflammasomes, and the biogenesis of lysosomes. 

“Having regarded lysosomes as mere degradative endpoint for many decades, it is becoming increasingly clear that these organelles are at the center of sensing and controlling cellular stress events to allow for a rapid cellular response to adapt to changing extracellular conditions,” Saftig and Puertollano wrote.

Informing Future Research

Thanks to modern research, we now have a better understanding of how lysosomes respond to damage. Disruptions in the integrity of the lysosomal membrane trigger a clever repair mechanism that seals the breached membrane. If the disruption is extensive, damaged lysosomes are simply eliminated via lysophagy. 

Lysosomes have also emerged as key organelles for calcium storage. Scientists have discovered that free calcium concentration within the lysosome is comparable to that in the endoplasmic reticulum. Lysosomal calcium signaling drives a number of cellular processes, such as lysosomal acidification, fusion with other cellular organelles, membrane trafficking, membrane repair, and the creation of contact sites with the endoplasmic reticulum. 

“In brief, lysosomes are the hub of several crucial cellular activities and signals in physiological conditions,” Zhang and colleagues concluded. “Detailed understanding of these mechanisms inspires the development of therapies targeting lysosomes.” 


Parenti G, Medina DL, Ballabio A. The rapidly evolving view of lysosomal storage diseasesEMBO Mol Med. 2021;13(2):e12836. doi:10.15252/emmm.202012836

Saftig P, Puertollano R. How lysosomes sense, integrate, and cope with stressTrends Biochem Sci. 2021;46(2):97-112. doi:10.1016/j.tibs.2020.09.004

Zhang Z, Yue P, Lu T, Wang Y, Wei Y, Wei X. Role of lysosomes in physiological activities, diseases, and therapyJ Hematol Oncol. 2021;14(1):79. doi:10.1186/s13045-021-01087-1