Nav: Home

Cell biology -- maintaining mitochondrial resilience

March 09, 2020

Mitochondria cannot autonomously cope with stress and must instead call on the cell for help. Molecular geneticists at Ludwig-Maximilians-Universitaet (LMU) in Munich have identified the long-sought signaling pathway which enables the organelles to do so.

Mitochondria are membrane-bounded intracellular organelles that supply the energy needed to power the biochemical operations required for cell function and survival. The energy is provided in the form of a compound called ATP, which can be hydrolyzed by specific enzymes to drive chemical reactions. When mitochondria are subjected to stress - owing to the accumulation of misfolded proteins, for example - their functional capacities are diminished. Degradation of mitochondrial function can have serious consequences for the affected cells, and potentially for the whole organism. In order to activate protective measures, mitochondria must transmit a distress signal into the surrounding cytosol. In a paper that appears in the leading scientific journal Nature, researchers led by Professor Lucas Jae at the LMU Gene Center now report that they have characterized the elusive signaling pathway that triggers the response to mitochondrial stress in human cells. Mitochondrial dysfunction is at the root of many serious disorders, and functional deterioration of these organelles is regarded as a major component of the aging process. The new findings are therefore of considerable significance in the search for new therapeutic approaches to the treatment of age-related diseases.

Although mitochondria retain a small set of genes required for their primary role as energy generators, they are unable to autonomously resolve stress. Instead, they must alert the cell to the developing emergency by sending a specific signal into the cytosol. This signal then triggers mechanisms that either dissipate the source of stress, or activate programmed cell death once the level of stress exceeds a specific threshold. Landmark studies in the nematode worm Caenorhabditis elegans have elucidated how this organism monitors the state of its mitochondria. However, the results show that the mode of action in worms differs from that in humans. Human cells respond to mitochondrial stress - and various other insults - by inducing a rather unspecific reaction known as the Integrated Stress Response (ISR) in the cytosol. "The signaling pathway that relays mitochondrial stress to the cell has eluded identification through classical biochemical approaches for over 20 years," says Jae. "So we decided to use a genetic strategy to tackle the problem."

Since normal human genomes contain two copies each of virtually every gene, Jae and his colleagues made use of 'haploid' cells, in which genes are present in only one copy. This allowed the researchers to randomly introduce millions of knockout mutations throughout the genome that would not be compensated for by the presence of a second gene copy. They then subjected the resulting mutant cells to mitochondrial stress and recovered mutants that responded aberrantly. "This unbiased genome-wide screening procedure revealed two mitochondrial key factors that are essential for the ability of the mitochondria to activate the cellular stress response. One of these is the enzyme OMA1, which can cleave target proteins, and the other is a barely studied protein called DELE1," Jae explains.

When mitochondria are exposed to stress, OMA1 becomes activated and induces the cleavage of the DELE1 protein into a shorter fragment. This fragment is then redistributed to the cytosol, where it binds to another enzyme called HRI, which in turn triggers the ISR. "HRI was thus far believed to be primarily required for the formation of red blood cells," says Jae. "Our study has now shown that it can also be activated by DELE1 in the context of mitochondrial perturbation."

According to the authors, these findings might open up new opportunities for therapeutic regulation of cellular stress responses. These could be relevant for conditions that are associated with mitochondrial malfunction - including debilitating, age-related neurodegenerative disorders, such as Parkinson's disease. Recently, drugs have been developed that can globally shut down the ISR. Although not tailored to a specific type of ISR-inducing stress, such compounds have been shown to have positive effects on cognition and learning in mice. However, unspecific inhibition of the ISR might also have undesirable effects, as the ISR, for instance, also mediates antiviral protection during infection. "In an alternative scenario, the cellular response to mitochondrial stress could be selectively modulated by manipulating the factors we have now identified," says Jae.

Ludwig-Maximilians-Universität München

Related Stress Articles:

How do our cells respond to stress?
Molecular biologists reverse-engineer a complex cellular structure that is associated with neurodegenerative diseases such as ALS
How stress remodels the brain
Stress restructures the brain by halting the production of crucial ion channel proteins, according to research in mice recently published in JNeurosci.
Why stress doesn't always cause depression
Rats susceptible to anhedonia, a core symptom of depression, possess more serotonin neurons after being exposed to chronic stress, but the effect can be reversed through amygdala activation, according to new research in JNeurosci.
How plants handle stress
Plants get stressed too. Drought or too much salt disrupt their physiology.
Stress in the powerhouse of the cell
University of Freiburg researchers discover a new principle -- how cells protect themselves from mitochondrial defects.
Measuring stress around cells
Tissues and organs in the human body are shaped through forces generated by cells, that push and pull, to ''sculpt'' biological structures.
Cellular stress at the movies
For the first time, biological imaging experts have used a custom fluorescence microscope and a novel antibody tagging tool to watch living cells undergoing stress.
Maternal stress at conception linked to children's stress response at age 11
A new study published in the Journal of Developmental Origins of Health and Disease finds that mothers' stress levels at the moment they conceive their children are linked to the way children respond to life challenges at age 11.
A new way to see stress -- using supercomputers
Supercomputer simulations show that at the atomic level, material stress doesn't behave symmetrically.
Beware of evening stress
Stressful events in the evening release less of the body's stress hormones than those that happen in the morning, suggesting possible vulnerability to stress in the evening.
More Stress News and Stress Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at