• Balancing lipids and recycling to preven

    From ScienceDaily@1:317/3 to All on Wed Apr 20 22:30:50 2022
    Balancing lipids and recycling to prevent mitochondrial meltdown

    Date:
    April 20, 2022
    Source:
    University of Helsinki
    Summary:
    An international team has discovered that the cellular
    balance of lipid droplets can impact the recycling of damaged
    mitochondria. These results have importance for cell survival and
    nervous system dysfunction.



    FULL STORY ========================================================================== Mitochondria release chemical energy and influence metabolic pathways
    that keep our cells and tissues healthy. Damage to these multifunctional powerhouses promotes cell death and disease.


    ==========================================================================
    To prevent "mitochondrial meltdown," our cells destroy defective
    mitochondria using a specialised recycling process termed
    "mitophagy." Mitophagy is implicated in many diseases and is a major pharmaceutical target for neurodegenerative disorders such as Parkinson's disease.

    Unexpected insights into metabolism, mitophagy and movement An
    international team of researchers studied a therapeutic molecule used to promote high levels of mitophagy and found that many metabolic pathways involving lipids were rapidly "rewired" before mitochondrial recycling
    took place. The results are now published in the EMBO Journal.

    "Surprisingly, the activity of a protein called DGAT1 is switched on to generate specialised structures known as lipid droplets, typically used
    to store fat. By impairing DGAT activity, we observed the disappearance
    of lipid droplets and reduced mitochondrial recycling, and cells were
    more vulnerable to stress and death," says Assistant Professor Thomas McWilliams, who led the study.

    Remarkably, when the DGAT1 gene was switched off in the brains of
    reporter flies, both mitophagy and motor function of the animals were
    severely impacted.

    A discovery forged from iron The study also makes unexpected insights
    into iron, an essential cofactor for life. The therapeutic molecule used
    to induce mitophagy is a chelator, a potent drug that depletes cellular
    iron and researchers found surprisingly rapid effects of its depletion
    on cellular metabolism. McWilliams says: "Iron homeostasis represents
    an ancient function of the mitochondrial network, and iron depletion
    after many hours promotes mitochondrial recycling.

    Postdoctoral researcher Maeve Long performed a series of ambitious
    experiments in my lab, profiling human cells after mere minutes of
    deferiprone exposure.

    Our collaborators then mapped very dynamic changes in metabolism in
    advance of mitophagy. This led us to study lipid crosstalk in further
    detail, with our Cambridge collaborators highlighting the significance
    of this synergy in vivo." Little is known about the factors that
    regulate physiological mitophagy, and this work opens new avenues
    for targeting this process. Commenting further, McWilliams adds:
    "Defective mitochondrial recycling is problematic for cell types that
    are very long-lived, such as nerve cells in the brain. Neurodegenerative pathology is often progressive, taking place over many years. When
    mitophagy is defective, it's reasonable that cells might adapt and
    utilise additional strategies to stay alive. Much more work is needed,
    but this is an unexpected and exciting find." The study was led by
    Assistant Professor Thomas McWilliams at the University of Helsinki in collaboration with Academy Professor Elina Ikonen and researchers at
    the Swedish Metabolomics Centre (Umeaa, SE), Dr Alex Whitworth at the
    MRC Mitochondrial Biology Unit (Cambridge, UK) and Dr Ian Ganley at the
    MRC Protein Phosphorylation and Ubiquitylation Unit (Dundee, Scotland).


    ========================================================================== Story Source: Materials provided by University_of_Helsinki. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Maeve Long, Alvaro Sanchez‐Martinez, Marianna Longo,
    Fumi Suomi,
    Hans Stenlund, Annika I Johansson, Homa Ehsan, Veijo T Salo,
    Lambert Montava‐Garriga, Seyedehshima Naddafi, Elina Ikonen,
    Ian G Ganley, Alexander J Whitworth, Thomas G McWilliams. DGAT1
    activity synchronises with mitophagy to protect cells from
    metabolic rewiring by iron depletion. The EMBO Journal, 2022;
    DOI: 10.15252/embj.2021109390 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220420092137.htm

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