Targeting lysosomes in human disease: from basic research to clinical applications

Abstract

In recent years, accumulating evidence has elucidated the role of lysosomes in dynamically regulating cellular and organismal homeostasis. Lysosomal changes and dysfunction have been correlated with the development of numerous diseases. In this review, we interpreted the key biological functions of lysosomes in four areas: cellular metabolism, cell proliferation and differentiation, immunity, and cell death. More importantly, we actively sought to determine the characteristic changes and dysfunction of lysosomes in cells affected by these diseases, the causes of these changes and dysfunction, and their significance to the development and treatment of human disease. Furthermore, we outlined currently available targeting strategies: (1) targeting lysosomal acidification; (2) targeting lysosomal cathepsins; (3) targeting lysosomal membrane permeability and integrity; (4) targeting lysosomal calcium signaling; (5) targeting mTOR signaling; and (6) emerging potential targeting strategies. Moreover, we systematically summarized the corresponding drugs and their application in clinical trials. By integrating basic research with clinical findings, we discussed the current opportunities and challenges of targeting lysosomes in human disease.

Fig. 1

Important events in the development of research into lysosomes as therapeutic targets. Since Christian de Duve discovered and named lysosomes in 1955, scientists have made significant contributions to reveal the structural characteristics and drugs of lysosomes and to connect lysosomes with important pathways such as autophagy, endocytosis, mTOR, and cell death, laying a foundation for the later use of lysosomes as therapeutic targets. Christian de Duve and Yoshinori Ohsumi won the Nobel Prize in 1974 and 2016, respectively, for their contributions to the discovery of lysosomes and the elucidation of autophagy mechanisms. CQ, chloroquine; LSDs, lysosomal storage disorders; CLEAR, coordinated lysosomal expression and regulation; NCCD, Nomenclature Committee on Cell Death

Fig. 2

Lysosomal structure and function. The lysosome is an acidic membrane-enclosed vesicular organelle containing a variety of hydrolases, and its activity and function are maintained by the channels or pump structures on its surface, such as v-ATPase, iron channels, and nutrient transporters. The lysosome acts not only as the endpoint of multiple trafficking routes, including autophagy, endocytosis, and phagocytosis, but also, as the platform for the recruitment and activation of mTOR, which regulates cell metabolism, growth, and differentiation. Ca²⁺ released from lysosomal calcium channels such as TRPML also regulates endocytic membrane trafficking, the nuclear transduction of TFEB, and the fusion of lysosomes with other cellular structures, such as autophagosomes and endosomes. However, the leakage of lysosomal contents such as cathepsins, ROS, Fe^2+/3+, and Ca²⁺ contributes to multiple forms of cell death. Exogenous antigens are processed into peptides by lysosomal proteases, and the lysosome also acts as a bilateral switch that mediate both pro-inflammatory and anti-inflammatory processes. The central location of the lysosome in the communication and convergence of multiple pathways determines its pivotal and irreplaceable role in cell metabolism, proliferation, differentiation, immunity, and death. Black arrows indicate positive regulation or metabolite flux, while red arrows indicate negative regulation. mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; Arg, arginine; TSC2, tuberous sclerosis complex; AMPK, AMP-activated protein kinase; TFEB, transcription factor EB; RTK, receptor tyrosine kinases; PP2A, protein phosphatase 2 A; TRPML1, transient receptor potential mucolipin 1; v-ATPase, vacuolar H + -adenosine triphosphatase; HSC70, heat shock cognate protein 70; LAMP2A, lysosome-associated membrane protein 2; LMP, lysosomal membrane permeability; MOMP, mitochondrial outer membrane permeabilization; CMA, chaperone-mediated autophagy; TGN, trans-Golgi network; CLEAR, coordinated lysosomal expression and regulation; ROS, reactive oxygen species; RAG, RAS-related GTP-binding protein; Unc-51-like kinase 1 (ULK1); PUMA, p53 upregulated modulator of apoptosis; BID, BH3 interacting domain death agonist; BAX, BCL2-associated X, apoptosis regulator; LDCD, lysosome-dependent cell death

Fig. 3

The biogenesis of lysosomes. Lysosomal biogenesis is a combination of cellular biosynthesis and endocytosis pathways. TRPML1 channel, calcineurin, PP2A, and mTORC1 jointly regulate the biosynthesis of lysosomal proteins by modulating the activation and nuclear translocation of TFEB. PP2A, protein phosphatase 2A; mTORC1, mammalian target of rapamycin complex 1; TGN, trans-Golgi network; TFEB, transcription factor EB; CLEAR, coordinated lysosomal expression and regulation

Fig. 4

Available strategies for targeting lysosomes in human disease and their corresponding drugs. Different colors indicate different targeting strategies: red, targeting lysosomal acidification; yellow, targeting lysosomal cathepsins; blue, targeting lysosomal membrane permeability and integrity; green, targeting lysosomal calcium signaling; purple, targeting mTOR signaling; gray, emerging targeting strategies with great potential. The action mechanisms of these drugs are highlighted in bold. mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; TRPML1, transient receptor potential mucolipin 1; LMP, lysosomal membrane permeability; ROS, reactive oxygen species; CMA, chaperone-mediated autophagy; CLEAR, coordinated lysosomal expression and regulation; TFEB, transcription factor EB; CQ, chloroquine; HCQ, hydroxychloroquine; QN, quinacrine; PLGA-aNP, poly(DL-lactide-co-glycolide) acidic nanoparticles; AAV, adeno-associated virus; rhCTSD, recombinant human pro-cathepsin D; rhPPCA, recombinant human protective protein/cathepsin A; ASM, acid sphingomyelinase; ZA, zoledronic acid; rhCTSD, recombinant human pro-Cathepsin D; DpdtC, Di-2-pyridylketone dithiocarbamate; Hsp70, heat shock protein 70; HspBP1, Hsp70 binding protein 1; 3,4-DC, 3,4-dimethoxychalcone; PI(3,5)P2, phosphatidyl-(3,5)-bisphosphate; MITF, melanogenesis-associated transcription factor; HPβCD, 2-Hydroxypropyl-β-cyclodextrin; PA, psoromic acid; 3-PEHPC, 3-(3-pyridyl)-2-hydroxy-2-phosphonopropanoic acid; RabGGTase, Rab geranylgeranyl transferase