Stressed mitochondria help cells to withstand lung infections, study suggests

Mitohormesis describes the fact that mild stress to a cell’s mitochondria can induce a series of responses that actually increase the cell’s health and viability. Acute respiratory distress syndrome (ARDS), which can finally result in fatality in old or susceptible persons, is brought on by several respiratory infections, such as influenza or COVID-19, which severely stress cells and organs.

“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. In a new study, Adrienne Mottis at EPFL and her colleagues have shown that one such strategy can exploit a biological phenomenon known as “mitohormesis”.

The primary energy-harvesting organelles of the cell, mitochondria, are continually watched by the cell’s “surveillance” systems. This ongoing quality monitoring can trigger adaptive compensating reactions referred to as “mitochondrial stress responses” if the mitochondria malfunction or are under stress.

“A mild level of mitochondrial stress can therefore be beneficial overall for the cell and the organism since the positive effect of these stress responses can overcome the negative effect of the initial stressor,” says Mottis who led the study. This idea is borne by previous studies showing that eliciting mitohormesis can extend lifespan by counteracting the effects of age-related or metabolic disorders.

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Because mitochondria are descended from bacteria, antibiotics may be used on them. To combat a variety of infections, including acne, cholera, plague, malaria, and syphilis, the researchers examined various antibiotics that could stress mitochondria and discovered novel molecules in the tetracycline family. Tetracyclines are a class of antibiotics that blocks the synthesis of mitochondrial proteins.

52 tetracyclines were examined by the researchers, and they chose unique compounds like 9-test-butyldoxycycline (9-TB) because they are very effective at inducing mitohormesis even at low dosages and have no antibiotic action, meaning they do not affect the host’s microbiota. When tested on mice, the chemicals led to moderate mitochondrial stress and advantageous mitohormetic responses that increased the mice’s tolerance to influenza virus infection.

The research demonstrates that 9-TB, without changing the microbiota, can help mice develop a resistance to influenza infection by lessening the degree of tissue damage and inflammation. The scientists add, “These results provide novel therapeutic options by targeting mitochondria and mitohormesis to combat inflammatory challenges and infections.”