Stressing Mitochondria Strengthens Cells Against ARDS

Researchers in Switzerland are suggesting a new strategy to combat acute respiratory distress syndrome (ARDS): mildly stressing cells’ mitochondria to elicit vitality-boosting cell responses.

ARDS can develop in respiratory infections like flu and COVID-19 and lead to death in the elderly and sensitive individuals. Mitochondria are the cell’s main energy-harvesting organelles and are constantly monitored by the cell’s surveillance systems. If the mitochondria malfunction or are subjected to stress—a process known as mitohormesis—this continuous quality control can activate adaptive compensatory responses. 

In a new study, Adrienne Mottis and colleagues at École polytechnique fédérale de Lausanne (EPFL) showed that inducing mitohormesis can be an effective strategy to treat ARDS.  “Novel therapeutic strategies to address ARDS, instead of fighting the infectious agent, could try to elicit the tolerance of the host organism towards the inflammatory challenge by boosting its natural adaptive stress responses,” says Professor Johan Auwerx at EPFL’s School of Life Sciences.

The study, published recently in The Journal of Clinical Investigation, demonstrated that the positive effect of these stress responses can overcome the negative effect of the initial stressor, Mottis says.

Because mitochondria have evolved from bacteria, they are susceptible to antibiotics. Therefore, the EPFL researchers looked at various antibiotics that could stress mitochondria and identified novel molecules in the family of the tetracyclines, a class of antibiotics that blocks the synthesis of mitochondrial proteins, and are used to counter a number of infections, such as acne, cholera, plague, malaria, and syphilis.

The researchers screened 52 tetracyclines and selected novel molecules, such as 9-tert-butyldoxycycline (9-TB), that are highly potent at triggering mitohormesis even when used at low doses, while having no antibiotic effect—that is, they do not disturb the host’s microbiome. Testing them on mice, the compounds triggered mild mitochondrial stress and beneficial mitohormetic responses that boosted the animals’ tolerance to infection by the influenza virus.

“Most importantly, our study shows that the 9-TB-triggered mitochondrial responses activate the ATF4 signaling pathway, a well-described response to multiple cellular stressors, and also mobilizes signaling pathways of innate immunity, the so-called type I interferon response,” says Auwerx.  “As a result, 9-TB improved the survival of mice subjected to a lethal influenza infection while it did not impact on the viral load. Resistant hosts fight infection by eliciting an immune response that reduces pathogen load, whereas tolerance refers to the mechanisms that limit the extent of organ dysfunction and tissue damage caused by infection, not necessarily impacting on pathogen load.”

The study shows that 9-TB can induce tolerance to influenza infection in mice by reducing the extent of inflammatory and tissue damage without affecting their microbiome. “These findings open innovative therapeutic avenues by targeting mitochondria and mitohormesis to fight inflammatory challenges and infections,” write the authors.

The results are supported by previous studies showing that eliciting mitohormesis can extend lifespan by counteracting the effects of age-related or metabolic disorders.