Lysosomal Dysfunction
Specificities
Impaired Autophagy: Reduced lysosomal degradation leading to accumulation of damaged organelles and proteins.
Lysosomal Storage Disorders (LSDs): Genetic diseases causing buildup of substrates within lysosomes.
Indicators
Lysosomal Membrane Permeabilization (LMP): Leakage of lysosomal contents, indicating dysfunction.
Cathepsin Release: Indicates lysosomal disruption and potential initiation of cell death.
Altered Lysosomal pH: Disruption of lysosomal acidity affecting enzyme activity.
Lysosomal Membrane Permeabilization (LMP): Leakage of lysosomal contents, indicating dysfunction.
Cathepsin Release: Indicates lysosomal disruption and potential initiation of cell death.
Altered Lysosomal pH: Disruption of lysosomal acidity affecting enzyme activity.
Inducers
Proton pump inhibitor: Bafilomycin A1
Intracellular alkalization: Ammonium chloride
Cathepsin inhibitors: Pepstatin A, E64d, Leupeptin
Proton pump inhibitor: Bafilomycin A1
Intracellular alkalization: Ammonium chloride
Cathepsin inhibitors: Pepstatin A, E64d, Leupeptin
Related Genes and Proteins
TFEB (Transcription Factor EB): Master regulator of lysosomal biogenesis and autophagy.
Cathepsins: Proteolytic enzymes critical for lysosomal function.
LAMP1/LAMP2: Integral lysosomal membrane proteins critical for maintaining lysosomal integrity.
TFEB (Transcription Factor EB): Master regulator of lysosomal biogenesis and autophagy.
Cathepsins: Proteolytic enzymes critical for lysosomal function.
LAMP1/LAMP2: Integral lysosomal membrane proteins critical for maintaining lysosomal integrity.
Mechanisms of Lysosomal Dysfunction
Deficient Lysosomal Enzyme Activity: Causes substrate accumulation and organellar stress.
Dysregulation of Lysosomal Biogenesis: Impaired transcriptional regulation by TFEB.
Deficient Lysosomal Enzyme Activity: Causes substrate accumulation and organellar stress.
Dysregulation of Lysosomal Biogenesis: Impaired transcriptional regulation by TFEB.
Organelle Relations to Lysosomal Dysfunction
Autophagy: Impaired fusion disrupts clearance, resulting in cell death.
Endoplasmic Reticulum (ER) : Excess late endosome-lysosome-ER contacts causes lysosomal Ca2+ deficits, leading to Endolysosomal collapse.
Mitochondria: Lysosomes play a critical role in supporting mitochondria and maintaining mitochondrial homeostasis.
Autophagy: Impaired fusion disrupts clearance, resulting in cell death.
Endoplasmic Reticulum (ER) : Excess late endosome-lysosome-ER contacts causes lysosomal Ca2+ deficits, leading to Endolysosomal collapse.
Mitochondria: Lysosomes play a critical role in supporting mitochondria and maintaining mitochondrial homeostasis.
Therapeutic Approaches
Neurodegenerative Diseases: Lysosomal dysfunction is observed in the early stages of Alzheimer's Disease and influences its progression.
Aging: Lysosomal dysfunction is associated with cellular senescence, where it impairs the degradation of damaged cellular components.
Cancer: Lysosomal pH change influences cystine storage and alters ferroptosis sensitivity in cancer.
Neurodegenerative Diseases: Lysosomal dysfunction is observed in the early stages of Alzheimer's Disease and influences its progression.
Aging: Lysosomal dysfunction is associated with cellular senescence, where it impairs the degradation of damaged cellular components.
Cancer: Lysosomal pH change influences cystine storage and alters ferroptosis sensitivity in cancer.
