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Linking Mitochondria to Neurological Disease


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you are welcome! there are reports showing altered mitochondrial distribution in stroke models, but we need to know more whether the redistribution is beneficial or detrimental

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heidi.mcbride

Good question. Doug Wallace’s lab has lovely EM images of mitochondria docked together where their cristae line up perfectly in heart muscle. They predicted that there would be junction like machineries to contact them and facilitate metabolic flux. And I recall at least one study seeing a connexin at mitochondria. I think it was connexin 43.

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s it easier to edit the mitochondrial genome?
People have used zinc finger nucleases and restriction enzymes, but CRISPR cannot be done right now.

Could we put nuclear genes in here that are either expressed in the mitochondria normally but are deficient or any old nuclear gene that is deficient
Yes, this is called allotopic expression and was done many years ago.

First stage in gene editing?

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gomezmoljfmedcol

how big a mitoc can be? and their most likely shape is…? sorry if too many questions

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heidi.mcbride

The causes of mitochondrial dysfunction can be many! From direct mendelian mutations to somatic drift in mtDNA mutations within tissues. Epigenetic work in mother mice fed different diets have also been shown to change mitochondrial behavior in the pups. But there are no drugs for mitochondrial disease or dysfunction that really work yet. In acute conditions of mito disease they can take CoQ10, but really these are not very useful. Lots still to be done!

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Connexins 32 (Fowler (2013) J Proteome Res 12:2597) and 43 (Boengler (2012) J Cell Mol Med 16:1649) have been found in mitos.

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heidi.mcbride

The shape of mitochondria can vary between tissues, as well as the electron densities within the matrix and inner membrane. So it’s a broad question to answer. But once you have a sense of the mito profiles in your tissue of interest, you generally look for cristae aberrations, sometimes you’ll see whorls of membrane, or big white spaces in the intermembrane space, revealing cristae remodelling. You can also sometimes see them contacting lysosomes, and the mitochondrial regions that lie against the lysosome can have very aberrant cristae. The best answer is just to look at loads of EM!

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the size of mito varies from tissue to tissue, the diameter of a mito can be anywhere from a few hundred nm (like in synapses) to a few micros (in muscles and sperm).

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gomezmoljfmedcol

does the ER has a membrane potential? some says no…and what about the electromot force that generate the outer membrane potential…is intrinsic or from the inner membrane (according to Dr V Lameshko)?

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heidi.mcbride

Certainly it has been shown many years ago by people like Gyorgy Hajnoscky that calcium release from the ER leads to depolarization in the mitochondria. When he added a bit of IP3 to the side of a long myotube he saw a wave of calcium loss from ER that followed the loss of TMRE stain in mitos. That was about 2005 and was beautiful. So yes, certainly the oscillations can be coupled. Just not so far directly with the frequency of neurotransmitter release.

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Some compounds can enter mitos passively, if they are not too hydrophilic. There are any number of transporters in mitos, some of which might bring in small molecules (e.g. pyruvate)

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I think that the field pretty much agrees that there is no membrane potential across the MOM.

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gomezmoljfmedcol

ok…currents from the inner membrane can go throug the outer…and cause some potential drop or not?

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heidi.mcbride

So we are losing this line now! Thank you all for listening and participating. It was a fun session and I hope we have inspired you to solve all things mitochondrial!
Best
Heidi

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