Lysosome‑dependent cell death, LDCD

1 Mechanism Overview

Lysosome‑dependent cell death (LDCD) is a regulated form of cell death driven by lysosomal dysfunction and lysosomal membrane permeabilization (LMP). Various cellular stressors, including oxidative stress (ROS accumulation), lysosomal iron overload, lipid metabolic disorders, autophagic stress, and lysosome‑targeting compound stimulation, can reduce lysosomal membrane stability and induce LMP.

Damaged lysosomes release large amounts of acidic hydrolases, particularly the cysteine proteases Cathepsin B (CTSB) and Cathepsin L (CTSL), as well as the aspartic protease Cathepsin D (CTSD), into the cytoplasm, thereby triggering downstream death signaling.

On one hand, Cathepsins can promote mitochondrial outer membrane permeabilization (MOMP) by cleaving the BH3‑only protein Bid, leading to cytochrome c release and activation of the caspase cascade, resulting in apoptosis‑like cell death. On the other hand, extensive Cathepsin‑mediated proteolysis can directly disrupt the cytoskeleton, nuclear proteins, and organelle homeostasis, inducing caspase‑independent cell death.

Furthermore, lysosomal damage can promote the release of damage‑associated molecular patterns (DAMPs) and activation of inflammatory signaling, thereby amplifying cellular injury responses.

Lysosome‑dependent cell death pathway schematic. Lysosome‑dependent cell death is initiated by lysosomal stress and membrane destabilization, leading to lysosomal membrane permeabilization (LMP)‑mediated release of cathepsins. Cathepsins subsequently induce mitochondrial dysfunction, proteolytic degradation, and activation of inflammatory signaling, ultimately resulting in apoptosis‑like, necrosis‑like, or caspase‑independent cell death.

2 Target List

Mechanism Module	Target / Detection Marker	Full Name	Biological Function	Detection Method
Lysosomal Identification and Function	LAMP1	Lysosome‑associated membrane glycoprotein 1	Classical lysosomal membrane protein; evaluates lysosome abundance and localization	WB / IF / IHC
	LAMP2	Lysosome‑associated membrane glycoprotein 2	Maintains lysosomal membrane stability and reflects lysosomal integrity	WB / IF
	LysoTracker	Lysosome‑specific acidic organelle fluorescent probe	Detects acidic lysosome abundance and acidification status	IF / Flow cytometry
	DQ‑BSA	Dye‑quenched bovine serum albumin	Evaluates lysosomal protein degradation capacity	Fluorescence assay
Lysosomal Membrane Permeabilization (LMP)	Galectin‑3 puncta	Galectin‑3 puncta formation	Marker of damaged lysosomal membranes	IF microscopy
	Galectin‑8 recruitment	Galectin‑8 recruitment to damaged lysosomes	Identifies damaged lysosomes	IF
	LAMP1 redistribution	Lysosome‑associated membrane glycoprotein 1 redistribution	Determines abnormalities in lysosomal membrane structure	IF
	Acridine orange release	Acridine orange release assay	Detects loss of lysosomal membrane integrity	Flow cytometry
Cathepsin Release and Execution	CTSB	Cathepsin B	Lysosomal cysteine protease	WB / IF / Activity assay
	CTSD	Cathepsin D	Lysosomal aspartic protease involved in protein degradation	WB / IF
	CTSL	Cathepsin L	Lysosomal cysteine protease involved in degradation of structural proteins	WB / IF
Lysosomal Regulation and Homeostasis	MCOLN1 (TRPML1)	Mucolipin‑1 / Transient receptor potential mucolipin 1	Lysosomal Ca²⁺ channel regulating calcium release	WB / IF
	TFEB	Transcription factor EB	Master regulator of lysosome biogenesis and repair	WB / IF
	ATP6V1A / ATP6V1B2	V‑type proton ATPase catalytic subunit A / subunit B2	Maintains V‑ATPase function and lysosomal acidification	WB
Oxidative Stress‑Induced Lysosomal Damage	ROS	Reactive oxygen species	Oxidative stress mediator	ROS probe assay
	4‑HNE	4‑Hydroxynonenal	Lipid peroxidation product	WB / IF
	MDA	Malondialdehyde	Lipid oxidation end product	Biochemical assay

3 Application Scheme

Biological event	Marker
Lysosome abundance	LAMP1, LAMP2
LMP	Galectin‑3 puncta
Lysosomal leakage	CTSB/CTSD redistribution
Lysosomal activity	LysoTracker, DQ‑BSA
Lysosomal Ca²⁺	TRPML1 (MCOLN1)
Mitochondrial damage	BAX, BAK, Cytochrome c
Apoptosis exclusion	Cleaved‑Caspase3, PARP

4 References

1. Boya P, Kroemer G. Lysosomal membrane permeabilization in cell death. Oncogene. 2008;27(50):6434‑6451. doi:10.1038/onc.2008.310.
2. Repnik U, Stoka V, Turk V, Turk B. Lysosomal cell death at a glance. Journal of Cell Science. 2014;127(1):3‑10. doi:10.1242/jcs.091181.
3. Wang F, Gómez‑Sintes R, Boya P. Lysosomal membrane permeabilization and cell death. Traffic. 2018;19(12):918‑931. doi:10.1111/tra.12613.