Lysosomal Stress Response (LSR): Physiological Importance and Pathological Relevance

Abstract

Extensive work has characterized endoplasmic reticulum (ER) and mitochondrial stress responses. In contrast, very little has been published about stress responses in lysosomes; subcellular acidic organelles that are physiologically important and are of pathological relevance. The greater lysosomal system is dynamic and is comprised of endosomes, lysosomes, multivesicular bodies, autophagosomes, and autophagolysosomes. They are important regulators of cellular physiology, they represent about 5% of the total cellular volume, they are heterogeneous in their sizes and distribution patterns, they are electron dense, and their subcellular positioning within cells varies in response to stimuli, insults and pH. These organelles are also integral to the pathogenesis of lysosomal storage diseases and it is increasingly recognized that lysosomes play important roles in the pathogenesis of such diverse conditions as neurodegenerative disorders and cancer. The purpose of this review is to focus attention on lysosomal stress responses (LSR), compare LSR with better characterized stress responses in ER and mitochondria, and form a framework for future characterizations of LSR. We synthesized data into the concept of LSR and present it here such that the definition of LSR can be modified as new knowledge is added and specific therapeutics are developed.

Keywords: Endoplasmic reticulum stress; Endosomes; Inter-organellar signaling; Lysosomes; Mitochondrial stress.

Fig 1.

Involvement of mTOR-TFEB in mediating lysosomal stress responses (LSR). Under unstressed conditions, mammalian target of rapamycin complex 1 (mTORC1) is localized on lysosome membranes and phosphorylates transcription factor EB (TFEB), which is a master regulator of lysosome biogenesis. Phosphorylated TFEB is bound by 14-3-3 protein promoting the sequestration of TFEB in the cytoplasm. Under stressful conditions, which can be caused by any drug, pathogen, or material that enters the endolysosome system (termed LSR inducers), lysosomes undergo lysosomal stress responses (labeled 1–9). We posit that during LSR, stressed lysosomes can use various signals, one of which being mTOR-TFEB signaling pathway to promote lysosome biogenesis. When lysosomes are stressed, mTORC1 is released from lysosome membranes, calcium is released through calcium permeable channels (depicted by blue cylinder) into the cytosol where it activates the cytosolic phosphatase calcineurin. Activated calcineurin dephosphorylates TFEB allowing it to translocate into the nucleus where it binds at the coordinated lysosomal expression and regulation (CLEAR) element of lysosome biogenesis genes. Subsequently, there is an increase of lysosome-related genes that lead to the possible restoration of stressed lysosomes. Thus, LSR may use lysosome biogenesis as one of the pathways to restore lysosome function.

Fig. 2

Lysosome stress response characteristics and examples of stimuli that cause LSR. Lysosomal stress responses can be characterized by (1) increased lysosome pH, (2) increased lysosome size, (3) lysosomal membrane permeabilization, (4) cationic efflux, (5) intracellular repositioning, (6) intraluminal protein aggregation, (7) intraluminal accumulation of LDL cholesterol, (8) redox catastrophe, and (9) bioenergetic crisis. Endogenous and exogenous stimuli such as the HIV-1 proteins Tat and gp120, drugs of abuse including methamphetamine and opioids, nanoparticles, LDL cholesterol, and chloroquine (CQ) and hydroxychloroquine (HCQ) can induce lysosome stress

Fig. 3

Flow diagram depicting responses and outcomes resulting from lysosomal stress. High levels of lysosomal stress (major) can lead to transcriptional/translational changes including increases in lysosome biogenesis. Lower levels of lysosomal stress (minor) can lead to selective autophagy and/or lysophagy. In either case, outcomes can include cell life or death

Fig. 4

Organellar stress responses. Resulting from acute and chronic stimuli and stressors, lysosomes can exhibit lysosome stress responses (LSR). LSR as characterized in the text and in Figure 2 is characterized by perinuclear to peripheral repositioning of lysosomes, increases in lysosome size, reduction in intralysosomal proton concentrations and decreases in cytosolic and extracellular pH, intraluminal accumulation of LDL cholesterol, increased misfolded protein aggregation, lysosomal membrane permeabilization, and efflux of calcium and iron from lysosomes. Endoplasmic reticulum (ER) and mitochondria exhibit their own stress responses, and these might be triggered by LSR. Mitochondria in response to increases in cytosolic iron and calcium act as cation sinks; when excessive results include increases in reactive oxygen species (ROS) leading to redox catastrophe and decreases in adenosine triphosphate (ATP) promoting bioenergetic crisis. A vicious cycle can result from LSR including (1) increases in ROS can cause further lysosome stress, (2) increases in cytosolic calcium can trigger calcium-induced calcium release from ER, and (3) increases in lipid accumulation and protein aggregation in ER can lead to ER stress. Therefore, LSR might be an early and upstream event that participates in inter-organellar stress responses.