Jump to content

Linking Mitochondria to Neurological Disease


neuronline_admin
 Share

Recommended Posts

neuronline_admin

Neurobiology of Disease Webinar and Live Chat


Our understanding of the cell biology of mitochondria has exploded in the last decade, providing a renewed understanding of their contribution to neurological diseases ranging from pediatric encephalomyopathies to Alzheimer’s, Huntington’s, and others.

Select faculty from the 2016 Neurobiology of Disease Workshop will continue the discussion, emphasizing mitochondrial motility and neurodegeneration, mitochondrial function in Alzheimer ’s disease, and the role of mitochondria in immunity and links to neuroinflammation. After the scientific presentations, join all the speakers here in the Neuronline Community for a live chat. Post your questions for the speakers in the replies below. *

In the live chat:

  • Heidi McBride, PhD, professor and Canada Research Chair in Mitochondrial Cell Biology at McGill University
  • Eric Schon, PhD, Lewis P. Rowland Professor of Neurology in genetics and development at Columbia University Medical Center
  • Xinnan Wang, PhD, assistant professor of neurosurgery at Stanford University School of Medicine
  • Phillip West, PhD, assistant professor of microbial pathogenesis and immunology at Texas A&M University Health Science Center

Watch the Webinar: Tuesday, July 18th at 1:00pm (EDT) Register now

Join the Live Chat: Tuesday, July 18th at 1:45pm (EDT) right here in the Neuronline Community

Can’t attend live? Register to watch on-demand.

Link back to webinar

*Current and inactive SfN members log in using SfN.org information. non-SfN members create a new account.


Want to learn more about neurobiology of disease?

Register now for the 2017 Neurobiology of Disease Workshop: Gene Therapy to Address Unmet Needs in Neurology, organized by Xandra Breakefield and Florian Eichler.

Link to comment
Share on other sites

We provide evidence that Alzheimer disease is functionally a disorder of ER-mitochondrial communication at contact sites between the two organelles (called mitochondria-associated ER membranes, or MAM), and that the biochemical cause of this altered ER-mitochondrial connectivity is perturbed lipid homeostasis.

Link to comment
Share on other sites

Cells balance their energy homeostasis and minimize oxidative stress by regulating mitochondrial function and transport and by eliminating dysfunctional mitochondria. I will give a brief overview of mitochondrial motility and quality control and their implication in neurodegeneration and regeneration.

Link to comment
Share on other sites

My presentation will focus on emerging roles for mitochondria in innate immunity and inflammation. I will briefly overview recent advances in the field and relate these findings to the pathobiology of mitochondrial and neurological diseases.

Link to comment
Share on other sites

  • 4 weeks later...
gomezmoljfmedcol

Very interesting. Could you please tell me if, in your opinion, this MAM-miscommunication imply altered calcium signaling? If yes, what kind of alteration? Thank you. Juan F Gomez-Molina, IGN

Link to comment
Share on other sites

Yes, calcium trafficking is altered. In AD, where ER-mito communication is increased, Ca trafficking from ER to mitos goe up (tyhis has been seen in AD patients and cells).

Link to comment
Share on other sites

Do any of you have any thoughts on cause/effect role of lipofuscin granules in the inflammatory and degenerative aspects of brain aging in particular?

Link to comment
Share on other sites

heidi.mcbride

Hi! Yes, you can find many papers reporting this in various diseases, and upon infections like HIV. Again, the mechanism of release is not yet established. It’s a new area of investigation for sure.

Link to comment
Share on other sites

gomezmoljfmedcol

What is the most likely velocity a mitochondria of a neuron can have, in general? in other words, if we point at random to a mitochondria, should we expect it is moving or resting? thanks…

Link to comment
Share on other sites

heidi.mcbride

Yes, I guess the idea is that such granules landing on the cell surface would active innate immune pathway. Not sure it’s been looked at specifically in neurodegeneration.

Link to comment
Share on other sites

Usually they accumulate inside to a pretty high degree especially in the Hippocampus and Substantia nigra. Are you say you would not expect them to have an immunological effect unless they found their way to the membrane?

Link to comment
Share on other sites

heidi.mcbride

Yes, I would so. The TLRs respond to crystals that land on the cell surface, etc., so this could look that that to the receptors.

Link to comment
Share on other sites

Question from registration:
Mitophagy seems to have exploded from Pink1/Parkin to BNIP Optineurin NDP52 FUNDC3 etc. Are these redundancies or are there specific triggers to these pathways for e.g. pathological vs physiological mitophagy?

Link to comment
Share on other sites

some studies suggests that membrane potential may affect the direction of mitochondria move, but other studies suggest otherwise. However, depolarization of membrane potential stops mito because Miro will be degraded.

Link to comment
Share on other sites

I’m a novice at immunology. I guess I am confused because the granules are generated over time inside the cell. At some point one would think the granule would be presented to the outside. There is also the problem that the granules are indestructible, so if the immune system gets activated it may not be able to complete its mission as it were.

Link to comment
Share on other sites

Are the motor proteins you discussed (milton, miro KHC) unique to mitochondrial motility, or are they involved in other organelle transport?

Link to comment
Share on other sites

heidi.mcbride

Good question! there are definitely PINK1/Parkin independent forms of mitophagy, but the real regulation of mitophagy in vivo is not so clear. Indeed, mitochondrial geneticists are always wishing that the dysfunctional mitochondria within these inherited diseases would be cleared. But they aren’t… So I think the jury is still out on the specific factors that initate mitophagy in vivo, and whether distinct molecular players respond to distinct damages.

Link to comment
Share on other sites

what is the level of change of calcium uptake by mitochondria in normal vs pathological condition, e.g. AD. In cardiac myocyte, it has been suggested that mitochondria does not act as a significant dynamic buffer. How much do we know about this in neuron?

Link to comment
Share on other sites

heidi.mcbride

You are right. Inside the cell they won’t do anything in terms of immunology. Only when released outside to active cell surface receptors would there be the trigger. The idea is to recruit macrophages, etc to the site so they may clean up the mess. But this can backfire if too many immune cells, microglia, etc get into the zone.

Link to comment
Share on other sites

Question from registration:
After traumatic brain injury mitochondrial dysfunction is known to magnify the primary injury. Can this be overcome by increased mitochondrial biogenesis? If so what would be the ligand or preconditioning stimuli?

Link to comment
Share on other sites

This is such a great question that I have also been wondering.

Is it easier to edit the mitochondrial genome?

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

First stage in gene editing?

Link to comment
Share on other sites

gomezmoljfmedcol

thanks!! does the membrane potential of the inner or outer membrane oscillate in neurons like in cardiac cells? if yes, frequency?

Link to comment
Share on other sites

In AD I don’t recall offhand what the fold-change is, but there are papers from Gyorgy Hajnoczky’s lab (Thomas Jefferson U) where they have measured this. Peter Hollenbeck (Purdue) may also have measured this in neurons.

Link to comment
Share on other sites

Yes, recent papers over the last 3-4 years indicate that mitos (and mtDNA) travel through “nanotunnels” from cell to cell, buut the mechanism is unknown, but exosomes and ectosomes have also been invoked as a mechanism.

Link to comment
Share on other sites

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?

Link to comment
Share on other sites

heidi.mcbride

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.

Link to comment
Share on other sites

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

Link to comment
Share on other sites

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.

Link to comment
Share on other sites

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?

Link to comment
Share on other sites

heidi.mcbride

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!

Link to comment
Share on other sites

shullugundi

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

Link to comment
Share on other sites

Please sign in to comment

You will be able to leave a comment after signing in

 Share

×
×
  • Create New...