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

--- up 7 weeks, 2 days, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)