Scientists investigate the impact of stress on mitochondria

Stress on Mitochondria
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A research team from Ludwig Maximilians University (LMU) has linked the impact of stress on mitochondria and neurodegenerative diseases. 

How was this link made between the impact of stress on mitochondria and neurodegenerative diseases?

LMU researchers have discovered a mechanism – the protein DELE1 – that detects organelle stress. Thus, this suggests a link between the impact of stress on mitochondria and neurodegenerative diseases.

Scientists have long posited a link between the impact of stress on mitochondria – little organelles in the interior of cells – and the ageing process as well as age-related illnesses, such as Alzheimer’s disease. “Many such illnesses cannot be cured – partly because we don’t yet understand fundamental mechanisms,” explained Professor Lucas Jae from LMU’s Gene Centre, Munich.

How does stress impact the mitochondria?

Frequently, mitochondrial dysfunction is triggered by the impact of stress on mitochondria. Stress can come from the cell, or originate in the mitochondrion itself, such as through reactive oxygen species – which occur during cellular respiration.

Additionally, 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,” said Dr Evelyn Fessler from the Gene Centre, Munich.

In Nature Communications, Fessler and Jae, together with Luisa Krumwiede, describe a mechanism whereby a special protein in humans, DELE1, detects the impact of stress on mitochondria while being imported into the mitochondria and reports different kinds to the cell. This can lead to different responses, such as repairs or induced cell death.

How did scientists conduct this study?

Two years ago, Jae’s team explored the question of how the impact of stress on the mitochondria is reported to the cell. Scientists discovered a novel signalling pathway consisting of the proteins OMA1, DELE1, and HRI, which looks after such tasks. 

“So, we knew which factors recognise mitochondrial stress, but we did not understand key aspects,” noted 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?”

What is the purpose of DELE1?

Scientists have discovered that DELE1 is continuously imported into the mitochondria and processed by proteases. Deep inside the mitochondria, DELE1 is then quickly degraded. Thus, there are molecules constantly passing through the outer and inner membranes of mitochondria to be imported.

However, the impact of stress on mitochondria causes this importing process to fail. New DELE1 molecules are detained 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.

Thus, the portion of the DELE1 protein that possesses the signalling 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,” noted Jae. This is how the impact of stress on mitochondria is detected.

Additionally, DELE1 also recognises 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 is important for cellular survival for DELE1 to detect the problem and inform the cell,” said Jae.

What are the next steps?

“Now that we understand the mechanism, we can investigate many different scenarios,” concluded Fessler. Scientists intend to discover how the decision is made regarding a repair phase due to a stress response or goes into programmed cell death because otherwise, it would present a danger. They also expect to be able to modulate the signalling pathway so that it favours cellular survival in times of mitochondrial stress, which is a possible approach for treating neurodegenerative diseases.


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