Linking Mitochondria to Neurological Disease



If there dysfunctional genes can be identified and replaced by non-overexpressive sequences, in theory that should be able to at least regulate some of the excessive activity right?


Also, it was very nicely shown in domapinergic neurons about 7 years ago by the Surmeier lab. Was an oscillation with about a 2 second pulse. Slower than neurotransmission. He linked it to the uncoupling proteins, but it’s not clear and not much has been done since then. But they do oscillate their potential.


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I guess I am expanding the question out even further. The small size and constant replication of the mtDNA might allow it to behave somewhat like a plasmid in bacteria allowing you to put in any kind of gene as long as it can be folded and targeted to where it is supposed to go. Maybe you could make it do RNAi via a gene in the mito which could supress sometthing as you say


do mitoc membranes oscillate with other membranes? any experiment?


Not in mammalians cells, at least today. Importing CAS9 is relatively easy to do, but importing the guide RNAs is more difficult. Finally, mammalian mitos have poor recombination systems, so getting the ligation step to work efficiently is problematic. Of course, one might be able to engineer these functions down the road.


Are the causes for mitochondrial dysfunction mostly genetic? Epigenetic? Results of both internal and external factors? Are there any neuroprotective agents that have been found to be beneficial?


I’m sure it could, but there are no good drugs yet. People are looking into NAD+ related therapies, and some other things. The Dawson lab has been working on links between Parkin and Paris in regulating biogenesis as a major issue in PD. Again, these things are all in the works, so good question!


Yes Exercise :slight_smile: Exercise fixes basically everything


what are the features that distinguish between stressed and healthy mitochondria in neurons (in an image taken using TEM)


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


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.


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?


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

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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!


are there limitations to doing this in a living human?


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


what is the potential drug delivery mechanisms that can reach and affect mito?


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!


Yes, not the least of which are ethical.