Mitochondria Play a Critical Role in Neuroinflammation, Neuron Cell Death, Study Reveals

Mitochondria Play a Critical Role in Neuroinflammation, Neuron Cell Death, Study Reveals

The release of fragmented or dysfunctional mitochondria — a cell’s powerhouse — by immune and structural cells inside the central nervous system is a critical step that triggers neuron death and the progression of human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), a study shows.

Led by researchers at the Stanford University School of Medicine, the study demonstrates that targeted inhibition of mitochondria fission may represent a new strategy for preventing nerve cell death across such disorders as ALS, Alzheimer’s disease, and Huntington’s disease.

This finding was reported in “Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration,” a study published in the journal Nature Neuroscience.

About seven years ago, a Stanford chemical and systems biology professor and her colleagues designed a small protein — which they called P110 — that had the ability to specifically block signals that could induce the fragmentation of mitochondria.

Now, the team led by Daria Mochly-Rosen, PhD, the senior author of the study, took a closer look at the impact of this protein on the nerve cells of the central nervous system.

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The scientists started by treating mice that had Alzheimer’s, Huntington’s, and ALS with P110 or a placebo, and collecting brain tissue samples for analysis. They found that mice that received placebo showed signs of activation of both microglia, or immune cells, and astrocytes, which are structural and supportive cells. Meanwhile, the mice treated with P110 showed evidence of less cell activation and slower disease progression.

Treatment with P110 also significantly reduced the amount of amyloid-beta aggregates, or clumps, which are linked with several neurological diseases. The protein also improved mitochondrial health and reduced neuroinflammation. The research showed P110 expanded the mice’s lifespans.

Next, the team cultured microglia cells in the lab. The scientists found that these cells released mitochondria and active signaling molecules into their surroundings when they were exposed to stressful stimulus, such as disease-related toxic protein aggregates. If astrocytes were cultured into this broth, the cells would become activated, suggesting a direct transfer of pro-inflammatory signals between microglia and astrocytes.

Additional detailed experiments revealed that the positive effects of P110 were mostly supported by preventing the release of damaged or fragmented mitochondria by microglia cells into the brain tissue milieu and consequent activation of astrocytes.

“Most people have thought that mitochondria situated outside of cells must be ghosts of dead or dying cells,” Mochly-Rosen said in a press release written by Bruce Goldman. “But we found plenty of high-functioning mitochondria in the culture broth, along with damaged ones. And the glial cells releasing them appear very much alive.”

The researchers note that even healthy cells routinely release mitochondria into their surrounding environment.

“Clinical and experimental studies have identified fragmented mitochondria in biofluids of patients afflicted by subarachnoid hemorrhage and of patients affected by stroke, which suggests that their presence in the extracellular space is a biomarker for neurodegeneration and disease severity,” the researchers said.

Indeed, the higher the amount of dysfunctional or fragmented mitochondria was in the surrounding tissue, the higher were the levels of neuroinflammation and neuron death.

The process of disease-related mitochondria fission was found to be mediated by the Drp1-Fis1 signaling pathway, which was blocked by P110. In contrast, treatment with P110 had no effect on another similar signaling pathway mediated by Drp1 and Mff proteins that is necessary for physiological mitochondria fission, which is required to maintain mitochondria health.

This selective effect also may represent a positive therapeutic feature of P110. The protein may support the transfer of more healthy mitochondrial into the neurons milieu while preventing the deleterious effects of disease-associated mitochondrial fission.

The team is still working to better understand how released damaged mitochondria can induce inflammation and neuronal cell death.

Mochly-Rosen and postdoctoral scholar Amit Joshi, PhD, the lead author of the study, have filed for a patent on P110 and its utility in Huntington’s disease, ALS, and other neurodegenerative diseases.

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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.

14 comments

  1. ronnie cooley says:

    I can’t help it but I believe that the ALS foundation is a bunch of hog wash. Because every time I read something about the ALS it always seems like all they are doing is something to say study suggests. Why can’t you say we have a cure for ALS today. I have lived with ALS for three years and have been keeping up with the ALS foundation progress. You are not any closer to a cure than you were three years ago. If this email pisses you off send me one back to change my mind. Please.

    • Jane Erway says:

      I AM new to this disease but have spent day and night researching it and what I found is that no new medicine in 25 years. Where is the money going that funds this? Certainly not for a cure as this disease can be cured from what I read. But no one wants to cure it then they would lose all that funding. Money is always first. Follow the money and you will find out why no cure.

    • Rosalie says:

      You are absolutely correct the als Association has not helped with treatment please join our fight for treatment we could have right now my husband was diagnosed in March if this year please join no more excuses FDA and ALSA protest and please look on YouTube als news now

  2. Per Maritz says:

    Det händer INGENTING! Bara lek, lek, lek. För 50 år sedan gick människan på månen. Inom ALS, o andra MND händer ingenting.

  3. Sonia says:

    I have to agree with Roonie. I have been diagnose with ALS,
    I read every article
    about all the studies and
    is the same answer ….
    Not answer, als is been here for so many years
    people are dying in 2-4 years and now is on young people couple weeks ago a men in his
    30 with two years of diagnosis died , so is not
    Only on old people , I understand they are so many studies going on but how you can qualify
    and what will be the best
    Is difficult to determine
    on your own ,, we need help from our government and our Doctors , like 15-20 years ago when HIV was killing so many people and they finally
    got it , they really work on it .
    Yes I get angry and frustrated and my brothers and sisters too,
    and the hard work and pain of our caregivers
    who watch as declined
    day by day ,

    • Jane Erway says:

      You are so right. My daughter cannot even get a second opinion and it took her 8 mos to get one. Doctors just shuffle you around.

  4. Michelle Osuski says:

    I agree. My Mom died of ALS. That’s 45 years ago and we are still studying.Now I have ALS as did my cousin who died also. Told I was too old for one study. Offered a medicine that maybe add 3-4 month’s to suffer. Other diseases get so much help. We are left out in the storm with no contact for how to get into studies or new meds. They are not sure how many have the disease as many are miss diagnosed or not diagnosed at all.

  5. There have been hundreds of drugs that have failed in tests to cure or treat Alzheimer’s. ALS also seems to defy a cure or a drug to slow down this illness for more then 3-5 months.With all the resources going into these diseases nothing has been accomplished,yet all I see are studies with little usable capabilities to help these patients. Are these scientists working in an echo chamber?

    • Jane Erway says:

      They are working in their banks and piling up the money for funding. Same old same old no cure because they lose funding and drug companies lose big time. No one cares about those suffering. Aids got all that from a certain group of people who got support from the media and Hollywood nuts. Regular people suffering don’t count.

  6. Linda Macdonald says:

    I was diagnosed with ALS in 2010 but I wonder if I really have it or something else? Once I was diagnosed they seem to stop looking for other reasons for my decline in health.

  7. Linda Macdonald says:

    I was diagnosed with ALS in 2010 but I wonder if I really have it or something else? Once I was diagnosed they seem to stop looking for other reasons for my decline in health.

  8. WIsdomAndReasonMike says:

    Please the ALS community needs more than studies. We need results or at least experiment on people willing to try because they have no other option left.
    Im in my 30s, just started a family and now I’m diagnosed with ALS. No 2nd chance, don’t pass go, death sentence in the worst way possible. To have another chance I would dedicate the rest of my time helping others, helping the planet,enjoying my life without asking for anything else ever.

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