Retromer-dependent defects in the sorting of these cargos impair autophagy and chaperone-mediated-autophagy (Kaushik and Cuervo, 2012) and decrease the content of hydrolases in the lysosome lumen (Seaman, 2004; Kaushik and Cuervo, 2012; McMillan et al., 2017). These hydrolases are necessary for aggregate and damaged organelle disposal via autophagy pathways
The Segura Lab at Duke, $50,000, to continue work on materials that promote healthy tissue regrowth after stroke. They say their experiments are difficult to fund because regrowing dead brain tissue is a long shot that requires a lot of out of the box thinking and is hard to explain. If you want to learn more about their work, check out http://seguralab.duke.edu. If you’re a stroke survivor and want to share your story, they’d like you to check out their Patient Connection page. They’re also looking for help spreading their ideas. If you have knowledge of both science and writing/visual communication, apply to work with them here; if you want to donate, you can do so here.
Even the best-studied genomes (those of humans, mice, nem-
atodes, fruit flies and budding yeast), have numerous genes of
unknown function. Notably, many of more recently functionally
characterized genes code for repair proteins115. Virtually all enzymes
exhibit side activities that often represent <0.1 % of the classical
activity and even sometimes <10−6
for the most specific enzymes.
The products generated by side activities have been neglected
until recently when it was realized that a new category of enzymes,
metabolite repair and clearance enzymes serve to destroy the most
important side products and avoid their accumulation, which might
otherwise be toxic, causing disease.
An example of a side activity is the production of l-2-hydroxy-
glutarate by l-malate dehydrogenase and lactate dehydrogenase, two
abundant enzymes. Their apparently tiny side activity (<10−6
pared to the regular activity) leads to the daily production of grams
of l-2-hydroxyglutarate in humans. An FAD-linked mitochondrial
enzyme reconverts l-2-hydroxyglutarate to α-ketoglutarate, avoid-
ing its accumulation, which is toxic particularly to the brain. The
metabolic disease l-2-hydroxyglutaric aciduria, which is due to
inactivating mutations in the repair enzyme, leads to progressive
neurodegeneration and increased incidence of brain tumors.
In glycolysis, there seems to be at least as many distinct repair
reactions as the 11 classical reactions of glycolysis116. This huge
diversity of side products related to glycolysis suggests that hun-
dreds and probably thousands of different side products may be
formed in cells. It is likely that only some of them are eliminated by
repair and clearance enzymes. But at least for those that are elimi-
nated, it is possible to evaluate their potential toxicity in cell-based
experiments. Such experiments have shown that some of the side
products are indeed extremely toxic.
methylguanine methyltransferase (MGMT) as an inducible degron for protein fusions. MGMT is a suicide protein that removes alkyl groups from the O6 position of guanine (O6G)åa
LYSOSOMAL REPAIR - https://www.nature.com/articles/s41586-022-05164-4
Longevity Depends on Prompt Repair of Lysosomal Breaches
"Universal" pathway behind cell recycling offers clues to combat aging
A phosphoinositide signalling pathway mediates rapid lysosomal repair
(Sept 2022) https://doi.org/10.1038/s41586-022-05164-4
The PITT (phosphoinositide-initiated membrane tethering and lipid transport) pathway may have therapeutic implications for a wide range of age-dependent diseases characterized by impaired lysosomal function.
Lysosomal dysfunction has been increasingly linked to disease and normal ageing1,2. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors3. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.
Intrepid biohacker gives himself infrared night vision, but at what price? - ExtremeTech this is not even remotely precise, but shows how some interventions are a #lowbar