Homocysteine disrupts lysosomal function by V-ATPase inhibition.

Area of Science:

• Cell Biology
• Metabolic Disorders
• Biochemistry

Background:

• Lysosomes are crucial for metabolic homeostasis and cellular signaling.
• The role of harmful metabolites in lysosomal dysfunction in metabolic diseases is poorly understood.

Purpose of the Study:

• To investigate how homocysteine, a metabolite linked to homocystinuria, affects lysosome function.
• To elucidate the molecular mechanisms underlying homocysteine-induced lysosomal damage.

Main Methods:

• Utilized Caenorhabditis elegans and mouse models.
• Analyzed the impact of homocysteine accumulation on lysosomal V-ATPase activity and lysosome morphology.
• Investigated homocysteine binding and homocysteinylation of V-ATPase.

Main Results:

• Homocysteine accumulation, caused by cystathionine β-synthase deficiency, leads to developmental arrest in C. elegans.
• Homocysteine directly inhibits V-ATPase by binding and homocysteinylating it, impairing lysosomal degradation.
• Observed enlarged lysosomes with cargo accumulation and membrane damage in C. elegans and Cbs-deficient mice, resembling lysosomal storage diseases.

Conclusions:

• Metabolite homocysteine directly damages lysosomes by inhibiting V-ATPase.
• Lysosomal impairment is a critical factor in the pathology of homocystinuria and related metabolic disorders.
• This study provides novel insights into metabolite-induced organelle damage and disease mechanisms.