15 replies to this topic

[ameldedic2]

What's is your next step with this information?

[enki273]

I cannot see how the article you presented does have any relevance to allotopic expression.
Note that
a) mitotic cells were used, whose mitochondrial depletion by ethidium bromide hardly reflects the low abundance of mitochondrial damage in these tissues in vivo and that
b) even if this were the case there remains the fact that clonally expanded mitochondria have a replicative advantage compared to wild-type ones, which will lead to another clonal expansion, rapidly undoing the restauration of mitochondrial function.

[henri]

To use a classical structure of saying things, this is quite interesting, but there is a problem. I think we would also need to remove the damaged mitochondria, because if we didn't, they would continue producing electrons that would make superoxide extracellularly. But maybe we could engineer mitochondria so that they'd scavenge stray electrons from their environment and put them to good use! Actually that seems kind of smart to me.

[enki273]

That is what mitochondria do physiologically: They import electron-carrying molecules like NADH and FADH2 and use the electrons to reduce oxygen to water.
"The environment" of the mitochondria is the cytosole. They cannot be engineered to take up extracellular electrons; the border between the extracellular space and the cell is the plasma membrane that actually exportselectrons.

[henri]

That is what mitochondria do physiologically: They import electron-carrying molecules like NADH and FADH2 and use the electrons to reduce oxygen to water.
"The environment" of the mitochondria is the cytosole. They cannot be engineered to take up extracellular electrons; the border between the extracellular space and the cell is the plasma membrane that actually exportselectrons.

Actually, I know that mitochondria are intracellular. But okay, I didn't express myself very clearly, and perhaps I wasn't thinking clearly enough either. What I kind of thought was that mitochondria could take up the electrons before they reach the plasma membrane. And as far as I know, mitochondria don't take up the reduced form of NADH and FADH2, but the oxidixed forms, which they then reduce with the electrons they extract from molecules like pyryvate.

One nice thing would probably be to have some powerful antioxidant in the extracellular space (and the cytosol as well), so that the electrons (or actually the superoxide they make when they react with molecular oxygen) woldn't make so much damage. On the other hand, I suppose it's easier to get food antioxidants into the cytosol than into mitochondria, so maybe this is actually something we can do already to some degree with supplements.

[enki273]

mitochondria do take up electron in the form of NADH and FADH2 , for example via the malate-aspartate shuttle and the glycerophosphate shuttle.
To be clear, electrons are mainly produced in two metabolic pathways: the glycolysis and the TCA or Krebs cycle. The latter is located within the mitochondrial matrix; the glycolysis is located in the cytosol, therefore its electrons must be imported into the mitochondria. This direction is reversed in respiration-deficient cells, where mitochondria export electrons first into the cytosol and than to the extracellular space.
Your idea concerning extracellular antioxidants is good in theory, and there is some evidence that most electrons in the extracellular space are taken up by ascorbic acid; but then, how do you explain the lack of increase in maximum lifespan even at very high doses of applied antioxidants?

[zoolander]

how do you explain the lack of increase in maximum lifespan even at very high doses of applied antioxidants?

it appears that the cells have a finite number of replications. Sometimes termed the "Hayflick limit". Once the cells have replicated "x" number of times the cell cycle becomes unstable and prone to uncontrolled replication i.e becomes cancerous.

Campisi has some great stuff on this

    Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors.

        * Campisi J.

    Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. jcampisi@lbl.gov

    Cells from organisms with renewable tissues can permanently withdraw from the cell cycle in response to diverse stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, is controlled by the p53 and RB tumor suppressor proteins and constitutes a potent anticancer mechanism. Nonetheless, senescent cells acquire phenotypic changes that may contribute to aging and certain age-related diseases, including late-life cancer. Thus, the senescence response may be antagonistically pleiotropic, promoting early-life survival by curtailing the development of cancer but eventually limiting longevity as dysfunctional senescent cells accumulate.

    PMID: 15734683 [PubMed - indexed for MEDLINE]

She basically puts forward the theory that the cells age to protect us from cancer. It's we either die or we lose control I guess, from the cells perspective.

Edited by zoolander, 12 December 2006 - 05:50 PM.

[enki273]

In vivo, mitotic cells show less mitochondrial damage than postmitotic ones. Adding ethidium bromide fully depletes the cell´s mitochondria - mitotic cells in the body never come in this situation, not even mitochondria of postmitotic cells are 100% damaged, so I´m afraid this is not a model that exactly reflects the situation in the body.
Secondly, the replicative advantage of faulty mitochondria is proven (1). I see no chance for healthy mitochondria to prevail in such an environment in the long run. AE and phagocytosis are two equally possible solutions, but as far as I see, adding healthy mitochondria is not.
To be clear, I found the article very interesting; no book about molecular biology has mentioned mitochondrial migration. My criticism was just directed to the claim that it could help with deficient mitochondria.
In how far is neuronal aging not dealt with by the alternatives?



(1) Shoubridge EA, Karpati G, Hastings KE. Deletion mutants are functionally dominant over wildtype
mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease. Cell 1990; 62:
43-49.

[enki273]

Thanks for your reply. There is in my opinion good reason to assume that a replicative advantage is an appropriate model of clonal expansion, but even if that was not so: How would we get rid of the faulty mitochondria? Furthermore, it cannot be avoided that new mtDNA damage arises and expands so that the transfer therapy would have to be assiduously continued.
What makes AE so attractive is the ultimacy of its success: Once established, mitochondria would never pose a problem anymore. Concerning the brain, as far as I understand the actual gene transfer to the nucleus would be achieved by suitable vectors, i.e. gene therapy with or without destroying the existing mtDNA. Not a single cell would have to be changed and all synaptic information would be preserved.

[henri]

mitochondria do take up electron in the form of NADH and FADH2 , for example via the malate-aspartate shuttle and the glycerophosphate shuttle.
To be clear, electrons are mainly produced in two metabolic pathways: the glycolysis and the TCA or Krebs cycle. The latter is located within the mitochondrial matrix; the glycolysis is located in the cytosol, therefore its electrons must be imported into the mitochondria.

Ok.

Your idea concerning extracellular antioxidants is good in theory, and there is some evidence that most electrons in the extracellular space are taken up by ascorbic acid; but then, how do you explain the lack of increase in maximum lifespan even at very high doses of applied antioxidants?

Good point - I can't tell.

[xanadu]

Our fearless leader Bush, has decreed that stem cell research will not go forward under his watch. Lets try to elect leaders from now on that are not living in the stone age. We need research like this to go forward and more importantly, for the fruits of the research to be made available to us.

I think it's too early to say that antioxidants don't extend lifespan. We have already found that people who ate a low fat high fiber diet live longer. These types of diets are naturally rich in antioxidants. It may be that some of the supplements we use are not that helpfull but new ones are always being found. Take resveratrol for example. I think avoiding mitochondrial damage in the first place is the best strategy. Repair after the fact is kind of pie in the sky but it sounds like it may happen. Prevention is still better than cure, IMO. Cheaper too.

[enki273]

The thing is that oxidative stress cannot be fully prevented. Every attempt of prevention must be incomplete. Furthermore, radicals do serve some beneficial purposes. Increasing antioxidant levels to astronomous heights is neither healthy nor desirable; besides, maximum lifespan is not improved by antioxidants.