An Overworked Powerhouse: A Boolean Model of Mitochondrial Dysfunction Associated Senescence in the Context of Aging Microglia

Katie Flieg head shot

Name: Katie Fleig
Major: Neuroscience
Advisors: Erzsebet Regan, Hilary Edgington; William Morgan (second reader)

Neuroinflammation is a hallmark of many neurodegenerative diseases such as Alzheimer’s and Parkinson’s. In the brain, inflammation is most often caused by a special type of brain immune cell called microglia. Depending on the type of damage the brain has sustained, the microglia can either enter into a pro-inflammatory state known as M1, or an anti-inflammatory state known as M2. In neurodegenerative diseases, either state can become chronic. One way this could happen is through Mitochondrial Dysfunction Associated Senescence (MiDAS), a form of cellular senescence arising from a feedback loop in which mitochondria stay in a hyperfused network for too long and cannot produce a sufficient amount of ATP to exit hyperfusion. The present study proposes a Boolean model of the MiDAS feedback loop, an in silico method that investigates the cellular conditions under which MiDAS can occur. The results show that MiDAS does not occur during a moderate amount of DNA damage, as well as a normal G1/S phase transition. MiDAS does occur from a high amount of DNA damage perpetuated by an abundance of Reactive Oxygen Species (ROS) but can be rescued by the knockdown or overexpression of several proteins and molecules involved in MiDAS. These results indicate several possibilities of further study that could ultimately lead to better treatments for neuroinflammation.

Posted in Comments Enabled, Independent Study, Symposium 2023 on April 14, 2023.

7 responses to “An Overworked Powerhouse: A Boolean Model of Mitochondrial Dysfunction Associated Senescence in the Context of Aging Microglia”

  1. Ellen Fleig says:

    Congratulations on your amazing accomplishment Katie!! We are so proud of you👏👏👏!!!
    Mom, Dad and Jackson

  2. Mrs. Lesley Karpiuk says:

    Oh my goodness, Katie! Congratulations on this outstanding accomplishment! You never cease to amaze me, and I’m so thankful you’ve kept in touch. So proud of you!
    Mrs. Karpiuk

  3. Katie Fleig says:

    Thanks guys!! Thank you for all your support!!

  4. Allison Ringold says:

    This looks so cool! Looking forward to seeing your presentation!!

  5. Katie Fleig says:

    Thanks, Allison! I can’t wait to see your poster!

  6. Erin Odya says:

    1. I’m pretty sure it’s not possible to be too interested in how our brains can malfunction!
    2. I can’t believe you said the mitochondria are powerhouse of the cell! Grrrr
    3. Are ROS just free radicals? Are they even called that anymore?
    4. What’s the difference between moderate and high amounts of damage?
    5. Why are you holding a giant tootsie roll?

    I wish I could be there for this. Though you’re probably glad I’m not! I’m quite proud of you and wouldn’t actually bombard you with questions anyway. And I’m totally kidding about #2. Kinda. Ok, not at all. LOL

  7. Katie Fleig says:

    Hi Miss Odya!! I’m so glad you checked out my work!

    1. True!!
    2. I know!! I just thought it would help remind people about where they’ve heard the name “mitochondria” before!!
    3. Yes, they are free radicals, and to my knowledge they are still called that, ROS is just a more specific names for the oxygen-containing free radicals produced by the electron transport chain to support the hydrogen gradient.
    4. So for this model, the difference is the “_H” modifier in the name of the node, but biologically from my understanding it’s essentially the point at which the DNA damage response isn’t favorable compared to apoptosis. Needless to say, it’s a bit arbitrary and is dependent upon whatever is happening in the cell. That’s my understanding and best guess!
    5. It’s a tradition at Wooster where whenever you turn in your thesis, you get a tootsie roll, and they made giant blow up ones for people to take pictures with!

    I would have loved to have you here, countless questions or not! I’m just happy you saw the webpage and had questions and comments! I am more than happy to answer all the questions you can think of, just email me and I’ll answer! Thank you so much for stopping by!