7 ms·

New role in cells suggested for ATP

62 points by alexholehouse 9y ago

reasonattlm 9y ago
For broader context, this might be used to help explain the well known link between the age-related decline in mitochondrial function (and consequence lowered production rate of ATP) and the age-related development of aggregates such as amyloids and tau. Aggregates are age-related, but one needs explanations as to why that is the case. Other proximate causes include declining cellular garbage collection mechanisms, aggregation of other proteins (protein A spurs aggregation of protein B), failure of mechanical clearance via peristaltic channels, and so forth. It's never just one thing. Like many lines of research manage to achieve, this finding adds a little more emphasis to the need to restore mitochondrial function in the old. Clearing damaged mitochondria, delivering replacement mitochondria to cells, allotopic expression of mitochondrial genes, and so forth.
- JumpCrisscross 9y ago
  Would it be encouraging to see if amyloid plaques dissolve in a concentrated aqueous solution of ATP? (Sorry if nonsensical. I am approaching the topic as a layman.)
  - deleted 9y ago
    [deleted]
  - entee 9y ago
    Had a different response here before but this quote from the article suggests maybe! "ATP kept proteins in boiled egg white from aggregating." It also appears the concentrations they're talking about are quite reasonable (10mM or so). That said, once an aggregate is formed you usually need pretty heroic methods to solubilize it. Much stronger detergents and denaturants at higher must be used, and in those cases you run into other problems. After solubilizing the aggregate, you have to fold the individual proteins back up. But now you have to do it in an environment where you 1.) a molecule that keeps the protein unfolded and 2.) a ton of other unfolded proteins around. You could slowly get rid of 1.) by dialysis or something similar. But when you have a bunch of unfolded proteins hanging around together, you almost always get aggregates. In practice, it's quite unlikely that ATP concentrations high enough to unfold an aggregate wouldn't unfold all sorts of other things. This would also mean the stuff you need to keep the rest of the cell working... so from a practical perspective this is unlikely to work.
- nonbel 9y ago
  >"Aggregates are age-related, but one needs explanations as to why that is the case." I don't think there is much mystery here. As cells divide they accumulate (genetic, and other types of) errors. One thing that happens is proteins/peptides are more likely to end up in their most thermodynamically stable state, since it requires constant maintenance to avoid it. http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html
  - ergothus 9y ago
    You're dismissing the idea of (1) proving the "obvious" solution or disproving it via data, and you're ignoring the "how". "There are errors" doesn't say where they are errors, and how those errors translate into behavior. If the hypothesis in the source article is help up by more data, that is actually a huge deal, not just confirming something we already knew.
    - nonbel 9y ago
      The review I shared contains many ideas along these lines. Basically the AA sequences seem to be selected to disfavor aggregation, so most mutations should increase formation: >"Many of the characteristics of proteins that enable the avoidance of aggregation, and amyloid formation in particular, are encoded by their amino acid sequences116. The elucidation of this code has enabled the identification of factors that determine the intrinsic aggregation propensity of these molecules117–119. Hence, it has been realized that globular proteins fold into structures that sequester aggregation-prone regions in their interior; in addition, typical features of the folding process, such as very high cooperativity, generate considerable kinetic barriers to the conversion of folded proteins into aggregation-prone species50,120. Furthermore, specific patterns of residues, such as alternating hydrophobic–hydrophilic stretches50,121, that tend to favour the amyloid state are commonly selected against during evolution119,121,122 or are otherwise neutralized by the insertion of highly aggregation-resistant residues, which are known as ‘gatekeepers’ (REFS 50,123)." Really I doubt in the end there will be any disease not associated with amyloid/aggregate formation.
  - subroutine 9y ago
dflock 9y ago
The subhead is more informative: > Known as an energy carrier, molecule can also solubilize proteins
subroutine 9y ago
While ATP may help to solubilize proteins, I don't find it surprising the cells under question have very high ATP concentrations. I take issue with this statement: > In addition to being an energy source for biological reactions, for which micromolar concentrations are sufficient, we propose that millimolar concentrations of ATP may act to keep proteins soluble. This may in part explain why ATP is maintained in such high concentrations in cells. Sure it's important for neurons to prevent amyloid-beta from aggregating, but we can explain why neurons have a super high (mM) ATP concentration for two other good reasons: 1. Unlike other cells, neurons conduct electrical signals. Every time a neuron fires it opens channels that allow sodium and potassium to flow through the membrane. Then, it needs to get those ions back across the membrane so the neuron can keep functioning. To do this neurons make prodigious use of Na/K-ATPase pumps, that exchange intracellular Na for extracellular K, against an electrochemical gradient. This is active transport that requires tons of ATP. In a typical animal cell active transport is a relatively small (~1/10th) portion of cellular energy expenditure compared to neurons (~7/10th). 2. ATP is used in actin filament polymerization. Each molecule of filamentous actin is coupled to an ATP molecule, and actin is found in neurons at mM concentrations. Actin is a major structural protein in cells, and plays a particularly important role in neurons. Actin helps create filopodial protrusions; if you compare a neuron to another type of cell you can immediately tell it's a protrusion machine. Even these protrusions (axons and dendrites) have protrusions (neurites and dendritic spines) that are constantly reorganizing to allow for structural plasticity among the brain's neural network connections. One of my dissertation projects was to simulate actin activity in neurons; for anyone's interested, here are some pretty neat visuals of this... Actin polymerization to create a dendritic spine: https://youtu.be/JH-hGjzhEFQ https://youtu.be/JH-hGjzhEFQ Small segment of a dendrite with surface receptor diffusion: https://www.youtube.com/embed/6ZNnBGgea0Y https://www.youtube.com/embed/6ZNnBGgea0Y Creating dendritic meshes in python: https://youtu.be/tDKUU0SqbSA https://youtu.be/tDKUU0SqbSA
- leemailll 9y ago
  I concur. To keep a neuron happy requires large amount of energy and ATP. Every electrophysiologist would know this from the very beginning.
- 9y ago
acjohnson55 9y ago
Sounds kind of like a surfactant (https://en.wikipedia.org/wiki/Surfactant https://en.wikipedia.org/wiki/Surfactant)

62 points by alexholehouse 9y ago

For broader context, this might be used to help explain the well known link between the age-related decline in mitochondrial function (and consequence lowered production rate of ATP) and the age-related development of aggregates such as amyloids and tau. Aggregates are age-related, but one needs explanations as to why that is the case. Other proximate causes include declining cellular garbage collection mechanisms, aggregation of other proteins (protein A spurs aggregation of protein B), failure of mechanical clearance via peristaltic channels, and so forth. It's never just one thing. Like many lines of research manage to achieve, this finding adds a little more emphasis to the need to restore mitochondrial function in the old. Clearing damaged mitochondria, delivering replacement mitochondria to cells, allotopic expression of mitochondrial genes, and so forth.

JumpCrisscross 9y ago
Would it be encouraging to see if amyloid plaques dissolve in a concentrated aqueous solution of ATP? (Sorry if nonsensical. I am approaching the topic as a layman.)
- deleted 9y ago
  [deleted]
- entee 9y ago
  Had a different response here before but this quote from the article suggests maybe! "ATP kept proteins in boiled egg white from aggregating." It also appears the concentrations they're talking about are quite reasonable (10mM or so). That said, once an aggregate is formed you usually need pretty heroic methods to solubilize it. Much stronger detergents and denaturants at higher must be used, and in those cases you run into other problems. After solubilizing the aggregate, you have to fold the individual proteins back up. But now you have to do it in an environment where you 1.) a molecule that keeps the protein unfolded and 2.) a ton of other unfolded proteins around. You could slowly get rid of 1.) by dialysis or something similar. But when you have a bunch of unfolded proteins hanging around together, you almost always get aggregates. In practice, it's quite unlikely that ATP concentrations high enough to unfold an aggregate wouldn't unfold all sorts of other things. This would also mean the stuff you need to keep the rest of the cell working... so from a practical perspective this is unlikely to work.
nonbel 9y ago
>"Aggregates are age-related, but one needs explanations as to why that is the case." I don't think there is much mystery here. As cells divide they accumulate (genetic, and other types of) errors. One thing that happens is proteins/peptides are more likely to end up in their most thermodynamically stable state, since it requires constant maintenance to avoid it. http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html http://www.nature.com/nrm/journal/v15/n6/full/nrm3810.html
- ergothus 9y ago
  You're dismissing the idea of (1) proving the "obvious" solution or disproving it via data, and you're ignoring the "how". "There are errors" doesn't say where they are errors, and how those errors translate into behavior. If the hypothesis in the source article is help up by more data, that is actually a huge deal, not just confirming something we already knew.
  - nonbel 9y ago
    The review I shared contains many ideas along these lines. Basically the AA sequences seem to be selected to disfavor aggregation, so most mutations should increase formation: >"Many of the characteristics of proteins that enable the avoidance of aggregation, and amyloid formation in particular, are encoded by their amino acid sequences116. The elucidation of this code has enabled the identification of factors that determine the intrinsic aggregation propensity of these molecules117–119. Hence, it has been realized that globular proteins fold into structures that sequester aggregation-prone regions in their interior; in addition, typical features of the folding process, such as very high cooperativity, generate considerable kinetic barriers to the conversion of folded proteins into aggregation-prone species50,120. Furthermore, specific patterns of residues, such as alternating hydrophobic–hydrophilic stretches50,121, that tend to favour the amyloid state are commonly selected against during evolution119,121,122 or are otherwise neutralized by the insertion of highly aggregation-resistant residues, which are known as ‘gatekeepers’ (REFS 50,123)." Really I doubt in the end there will be any disease not associated with amyloid/aggregate formation.
- subroutine 9y ago

dflock 9y ago

The subhead is more informative: > Known as an energy carrier, molecule can also solubilize proteins

subroutine 9y ago

While ATP may help to solubilize proteins, I don't find it surprising the cells under question have very high ATP concentrations. I take issue with this statement: > In addition to being an energy source for biological reactions, for which micromolar concentrations are sufficient, we propose that millimolar concentrations of ATP may act to keep proteins soluble. This may in part explain why ATP is maintained in such high concentrations in cells. Sure it's important for neurons to prevent amyloid-beta from aggregating, but we can explain why neurons have a super high (mM) ATP concentration for two other good reasons: 1. Unlike other cells, neurons conduct electrical signals. Every time a neuron fires it opens channels that allow sodium and potassium to flow through the membrane. Then, it needs to get those ions back across the membrane so the neuron can keep functioning. To do this neurons make prodigious use of Na/K-ATPase pumps, that exchange intracellular Na for extracellular K, against an electrochemical gradient. This is active transport that requires tons of ATP. In a typical animal cell active transport is a relatively small (~1/10th) portion of cellular energy expenditure compared to neurons (~7/10th). 2. ATP is used in actin filament polymerization. Each molecule of filamentous actin is coupled to an ATP molecule, and actin is found in neurons at mM concentrations. Actin is a major structural protein in cells, and plays a particularly important role in neurons. Actin helps create filopodial protrusions; if you compare a neuron to another type of cell you can immediately tell it's a protrusion machine. Even these protrusions (axons and dendrites) have protrusions (neurites and dendritic spines) that are constantly reorganizing to allow for structural plasticity among the brain's neural network connections. One of my dissertation projects was to simulate actin activity in neurons; for anyone's interested, here are some pretty neat visuals of this... Actin polymerization to create a dendritic spine: https://youtu.be/JH-hGjzhEFQ https://youtu.be/JH-hGjzhEFQ Small segment of a dendrite with surface receptor diffusion: https://www.youtube.com/embed/6ZNnBGgea0Y https://www.youtube.com/embed/6ZNnBGgea0Y Creating dendritic meshes in python: https://youtu.be/tDKUU0SqbSA https://youtu.be/tDKUU0SqbSA

leemailll 9y ago
I concur. To keep a neuron happy requires large amount of energy and ATP. Every electrophysiologist would know this from the very beginning.
9y ago

acjohnson55 9y ago

Sounds kind of like a surfactant (https://en.wikipedia.org/wiki/Surfactant https://en.wikipedia.org/wiki/Surfactant)