Failure of lysosomal acidification and endomembrane network in neurodegeneration

 Your competent? doctor figured out what to do with lysosomes over a decade ago, right? Oh no, FUCKING INCOMPETENCE OCCURRED!

I take no prisoners in trying to get stroke solved; I'll step all over supposed stroke medical 'professionals' until they actually start working on 100% recovery!

lysosomes (5 posts to October 2012)

Failure of lysosomal acidification and endomembrane network in neurodegeneration

• Seo-Hyun Kim, 
• Young-Sin Cho & 
• Yong-Keun Jung 

Experimental & Molecular Medicine (2025)Cite this article

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Abstract

Lysosomes have emerged as central hubs in the regulation of the endomembrane system, extending beyond degradation to coordinate organelle communication. Central to this regulatory role is vacuolar-type H+-ATPase (V-ATPase), a proton pump that acidifies the lysosomal lumen to enable hydrolase activity and support proteostasis. In addition to its lysosomal functions, V-ATPase influences the physiology of other organelles, including the endoplasmic reticulum (ER), Golgi apparatus and mitochondria, through both direct and indirect mechanisms involving acidification-dependent processes, such as protein folding, vesicular trafficking and stress responses. V-ATPase dysfunction compromises interorganelle communication through multiple mechanisms, including impaired calcium and lipid exchange at contact sites, disrupted organelle positioning and defective autophagic and stress signaling. In neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, V-ATPase impairment contributes to lysosomal storage pathology, ER stress, Golgi fragmentation and mitochondrial dysfunction. ER–endolysosome tethering proteins and mitochondria–lysosome contacts are particularly sensitive to pH and trafficking defects. These disruptions result in a cascade of organelle dysfunction and contribute to disease progression. Here, in this Review, we highlight how V-ATPase governs both local lysosomal function and broader organelle network integrity, positioning it as a critical regulator of endomembrane homeostasis and a potential therapeutic target in neurodegenerative conditions.