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Mitochondrial stress causes neuronal dysfunction via an ATF4-dependent increase in L-2-hydroxyglutarate (2019) Hunt et al

Discussion in 'Health News and Research unrelated to ME/CFS' started by MyalgicE, Nov 23, 2019.

  1. MyalgicE

    MyalgicE Senior Member (Voting Rights)

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    Abstract
    Mitochondrial stress contributes to a range of neurological diseases. Mitonuclear signaling pathways triggered by mitochondrial stress remodel cellular physiology and metabolism. How these signaling mechanisms contribute to neuronal dysfunction and disease is poorly understood. We find that mitochondrial stress in neurons activates the transcription factor ATF4 as part of the endoplasmic reticulum unfolded protein response (UPR) in Drosophila. We show that ATF4 activation reprograms nuclear gene expression and contributes to neuronal dysfunction. Mitochondrial stress causes an ATF4-dependent increase in the level of the metabolite L-2-hydroxyglutarate (L-2-HG) in the Drosophila brain. Reducing L-2-HG levels directly, by overexpressing L-2-HG dehydrogenase, improves neurological function. Modulation of L-2-HG levels by mitochondrial stress signaling therefore regulates neuronal function.

    http://jcb.rupress.org/content/early/2019/10/29/jcb.201904148

    Uni media release:

    Mitochondria, the organelle that powers most cells in the body, may be the canary in the coal mine for neurological disease, according to new findings published in the Journal of Cell Biology.

    Mitochondrial stress and dysfunction have long been suspected as an early step in diseases like Parkinson’s or Alzheimer’s disease, but Northwestern scientists have uncovered a mechanism that may explain how.

    The study found that mitochondrial stress in neurons can cause an enzyme imbalance that contributes to neuronal dysfunction and death. Reversing this imbalance showed promise in cell models, sketching an outline of a future therapy,

    https://www.feinberg.northwestern.edu/_rwd/head.php
     
    alktipping, Sly Saint, Wonko and 4 others like this.
  2. Andy

    Andy Committee Member & Outreach

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