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Autophagy is markedly impaired in Alzheimer’s disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models. Interrogation of neuronal autophagy in vivo in Alzheimerʼs disease mouse models identified deficient autolysosome acidification as the basis for extreme autophagic stress, yielding β-amyloid accumulation within intact neurons, which are the main source of senile plaques.

Exciting new discoveries have transformed the view of the lysosome from a static organelle dedicated to the disposal and recycling of cellular waste to a highly dynamic structure that mediates the adaptation of cell metabolism to environmental cues. Lysosome-mediated signalling pathways and transcription programmes are able to sense the status of cellular metabolism and control the switch between anabolism and catabolism by regulating lysosomal biogenesis and autophagy. The lysosome also extensively communicates with other cellular structures by exchanging content and information and by establishing membrane contact sites. It is now clear that lysosome positioning is a dynamically regulated process and a crucial determinant of lysosomal function. Finally, growing evidence indicates that the role of lysosomal dysfunction in human diseases goes beyond rare inherited diseases, such as lysosomal storage disorders, to include common neurodegenerative and metabolic diseases, as well as cancer. Together, these discoveries highlight the lysosome as a regulatory hub for cellular and organismal homeostasis, and an attractive therapeutic target for a broad variety of disease conditions.Lysosomes are mainly associated with cellular waste disposal. But it has recently been discovered that by integrating various environmental cues, they have a broader role as regulatory hubs for cellular and organismal homeostasis. The modulation of lysosome function could thus be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.

Every cell must satisfy basic requirements for nutrient sensing, utilization and recycling through macromolecular breakdown to coordinate programmes for growth, repair and stress adaptation. The lysosome orchestrates these key functions through the synchronised interplay between hydrolytic enzymes, nutrient transporters and signalling factors, which together enable metabolic coordination with other organelles and regulation of specific gene expression programmes. In this Review, we discuss recent findings on lysosome-dependent signalling pathways, focusing on how the lysosome senses nutrient availability through its physical and functional association with mechanistic target of rapamycin complex 1 (mTORC1) and how, in response, the microphthalmia/transcription factor E (MiT/TFE) transcription factors exert feedback regulation on lysosome biogenesis. We also highlight the emerging interactions of lysosomes with other organelles, which contribute to cellular homeostasis. Lastly, we discuss how lysosome dysfunction contributes to diverse disease pathologies and how inherited mutations that compromise lysosomal hydrolysis, transport or signalling components lead to multi-organ disorders with severe metabolic and neurological impact. A deeper comprehension of lysosomal composition and function, at both the cellular and organismal level, may uncover fundamental insights into human physiology and disease.Lysosomes orchestrate key cellular functions such as nutrient sensing, degradation of macromolecules and stress adaptation. This Review discusses the integration of signalling pathways at the lysosome and highlights the interaction of lysosomes with other organelles and mechanisms that ensure lysosome homeostasis.

Defective lysosomal function has been implicated in diseases ranging from rare lysosomal storage disorders to more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. Here, Muller and colleagues provide an overview of the physiological and pathological roles of lysosomes and assess the progress and opportunities for therapeutically targeting lysosomal proteins and processes.

Long known as terminal degradation stations, lysosomes have emerged as sophisticated signalling centres that govern cell growth, division and differentiation. Lysosomes interface physically and functionally with other organelles, and the master regulator mechanistic target of rapamycin complex 1 kinase is activated on lysosomes in response to nutrient and growth factor inputs. Lysosomes also enable autophagy, a ‘self-eating’ process essential for quality control and stress adaptation. Faulty execution of lysosomal growth and catabolic programmes drives cancer, neurodegeneration and age-related diseases. In this Review, Lawrence and Zoncu discuss the central role of the lysosome in cellular metabolism, including in macromolecular catabolism and nutrient recycling, and organelle crosstalk. They highlight the emerging function of the lysosome as a centre for nutrient sensing and metabolic signal transduction.

Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation. Several organelle membranes make contact in the cell, with many contacts being spatially segregated sites dedicated to specific functions. Here, Hao et al. show that hypoxia increases mitochondria-lysosome contacts, leading to engulfment and degradation of the mitochondria.

Lysosomal dysfunction has been increasingly linked to disease and normal ageing 1 , 2 . Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors 3 . Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function. Lysosomal membrane damage triggers a lipid signalling pathway that repairs lysosomes via lipid transport at newly established endoplasmic reticulum–lysosomal membrane contact sites.

Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs. Kuchitsu et al. show that STING-positive vesicles of a recycling endosome origin are encapsulated into lysosomes after STING ubiquitination and this process requires ESCRT proteins Tsg101 and Vps4.

Formation of inter-organelle contacts between mitochondria and lysosomes, regulated by lysosomal RAB7 GTP hydrolysis, allows for bidirectional regulation of mitochondrial and lysosomal dynamics. Contacts inside cell walls Cellular organelles such as mitochondria and lysosomes are dynamic entities that communicate with each other not just through vesicular trafficking but also by direct, albeit transient, contact between different organelles. Dimitri Krainc and colleagues report the existence of inter-organelle contacts between mitochondria and lysosomes—a phenomenon that seems to be independent of the association between damaged mitochondria and lysosomes in the context of the degradative process of mitophagy. The authors also identify organelle-specific molecules that mediate the tethering between these two organelles and demonstrate that lysosome–mitochondrion contacts allow bidirectional regulation of the dynamics of these organelles. Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases 1 , 2 , 3 , 4 . Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism 5 . Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase 1 , which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identified the formation and regulation of mitochondria–lysosome membrane contact sites using electron microscopy, structured illumination microscopy and high spatial and temporal resolution confocal live cell imaging. Mitochondria–lysosome contacts formed dynamically in healthy untreated cells and were distinct from damaged mitochondria that were targeted into lysosomes for degradation 6 , 7 . Contact formation was promoted by active GTP-bound lysosomal RAB7, and contact untethering was mediated by recruitment of the RAB7 GTPase-activating protein TBC1D15 to mitochondria by FIS1 to drive RAB7 GTP hydrolysis and thereby release contacts. Functionally, lysosomal contacts mark sites of mitochondrial fission, allowing regulation of mitochondrial networks by lysosomes, whereas conversely, mitochondrial contacts regulate lysosomal RAB7 hydrolysis via TBC1D15. Mitochondria–lysosome contacts thus allow bidirectional regulation of mitochondrial and lysosomal dynamics, and may explain the dysfunction observed in both organelles in various human diseases.

Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1) through an unknown process. Here, we show that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing V-ATPase-mediated acidification of lysosomes. When mTORC1 is active, peripheral V-ATPase V 1 domains reside in the cytosol where they are stabilized by association with the chaperonin TRiC. Consequently, most lysosomes display low catabolic activity. When mTORC1 activity declines, V-ATPase V 1 domains move to membrane-integral V-ATPase V o domains at lysosomes to assemble active proton pumps. The resulting drop in luminal pH increases protease activity and degradation of protein contents throughout the lysosomal population. These results uncover a principle by which cells rapidly respond to changes in their nutrient environment by mobilizing the latent catabolic capacity of lysosomes. mTORC1 blocks lysosomal nutrient generation. Here, the authors show that mTORC1 inactivation triggers V-ATPase assembly, which rapidly initiates lysosomal acidification and degradation of protein contents throughout the lysosomal population.