Cell biology: How mitochondria report stress
Date:
April 7, 2022
Source:
Ludwig-Maximilians-Universita"t Mu"nchen
Summary:
Researchers have discovered the mechanism by which the protein DELE1
detects organelle stress. This offers a possible new approach for
treating neurodegenerative diseases.
FULL STORY ==========================================================================
LMU researchers have discovered the mechanism by which the protein DELE1 detects organelle stress. This offers a possible new approach for treating neurodegenerative diseases.
========================================================================== Researchers have long posited a link between dysfunctions in mitochondria, little organelles in the interior of cells, and the aging process and age- related illnesses, such as Alzheimer's disease. "Many such illnesses
cannot be cured -- partly because we don't yet understand fundamental mechanisms," says Professor Lucas Jae from LMU's Gene Center Munich.
Frequently, the mitochondrial dysfunction is triggered by various forms of stress -- this much is known. Stress can come from the cell or originate
in the mitochondrion itself, such as through reactive oxygen species,
which occur during cellular respiration. Although they have their
own genome, mitochondria are incapable of responding independently to
stress. "This means that disturbances must be reported to the rest of
the cell," explains Dr. Evelyn Fessler from the Gene Center Munich.
In Nature Communications, Fessler and Jae, together with Luisa Krumwiede, describe a mechanism whereby a special protein in humans, DELE1, detects various kinds of stress while being imported into mitochondria and reports
them to the cell. This can lead to different responses, such as repairs
or induced cell death.
Known molecule, unknown mechanism Two years ago, Jae's team explored
the question as to how mitochondrial stress is actually reported to the
cell. The researchers found a new signaling pathway consisting of the
proteins OMA1, DELE1, and HRI, which looks after such tasks.
"So we knew which factors recognize mitochondrial stress, but we didn't understand key aspects," recalls Jae. "How does the DELE1 signal travel
from the mitochondrion into the cytoplasm of the cell? And how can
DELE1, as an individual protein, detect the many different types of
stress?" Now the researchers have found answers. DELE1 is continuously imported into the mitochondria and processed by proteases. Deep inside
the mitochondria, DELE1 is then quickly degraded. As such, there are
molecules constantly passing through the outer and inner membranes of mitochondria in order to be imported.
Mitochondrial stress causes this importing process to fail. New
DELE1 molecules are arrested on their way into the mitochondria and,
depending on the source of the disturbance, are either cut by OMA1 or
remain uncleaved outside the organelles. In any case, the portion of
the DELE1 protein that possesses the signaling effect is unmasked in the cytosol. "All the different types of stress lead to one of the sub-steps involved in the importing and processing of DELE1 coming to a halt,"
summarizes Jae. This is how mitochondrial stress is detected.
DELE1 also recognizes dysfunctions in the mitochondrial enzymes PITRM1
and MPP.
In neurodegenerative diseases, these enzymes are mutated. "Specifically
in connection with such defects, we have observed that it's important for cellular survival for DELE1 to detect the problem and inform the cell,"
notes Jae.
What happens next? "Now that we understand the mechanism, we can
investigate many different scenarios," reports Fessler. The researchers
want to discover how the decision is made as to whether a cell enters a
repair phase due to a stress response or goes into programmed cell death, because otherwise it would present a danger. They also hope to be able
to modulate the signaling pathway such that it favors cellular survival
in times of mitochondrial stress: a possible approach for treating neurodegenerative diseases.
========================================================================== Story Source: Materials provided by
Ludwig-Maximilians-Universita"t_Mu"nchen. Note: Content may be edited
for style and length.
========================================================================== Journal Reference:
1. Evelyn Fessler, Luisa Krumwiede, Lucas T. Jae. DELE1 tracks
perturbed
protein import and processing in human mitochondria. Nature
Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-29479-y ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220407141936.htm
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