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 mitochondria cells and organs.
According to Professor Johan Auwerx of the School of Life Sciences at EPFL, “novel treatment techniques to address ARDS could try to elicit the host organism’s tolerance towards the inflammatory challenge by enhancing its natural adaptive stress responses.”
In a recent study, Adrienne Mottis from EPFL and her coworkers demonstrated how one such tactic can take advantage of a biological phenomenon called “mitohormesis.” Mild stress to a cell’s mitochondria can result in a chain of reactions that actually improve the cell’s health and viability. This phenomenon is known as mitohormesis.
The primary energy-harvesting organelles of the cell, mitochondria, are constantly watched by the cell’s “surveillance” systems. This ongoing quality control can trigger adaptive compensating reactions referred to as “mitochondrial stress responses” if the mitochondria malfunction or are under stress.
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Since the favourable effects of these stress responses can outweigh the detrimental effects of the initial stressor, a low degree of mitochondrial stress may therefore be advantageous for the cell and the organism as a whole, according to study leader Mottis. This theory is supported by earlier research that demonstrates how inducing mitohormesis can lengthen lifespan by reducing the consequences of ageing or metabolic diseases.
Because mitochondria have evolved from bacteria, they are susceptible to antibiotics. Therefore, the 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.
52 tetracyclines were examined by the researchers, and they chose unique compounds like 9-test-butyldoxycycline (9-TB) because they are highly 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 mild mitochondrial stress and advantageous mitohormetic responses that increased the mice’s tolerance to influenza virus infection.
“Most critically, our study demonstrates that the 9-TB-triggered mitochondrial responses mobilise signalling pathways of innate immunity, the so-called type I interferon response, and activate the ATF4 signalling pathway, a well-described response to various cellular stresses,” continues Auwerx.
H further said, “As a result, while having no effect on the viral load, 9-TB increased the survival of mice that had been exposed to a deadly influenza illness. While tolerance refers to the mechanisms that restrict the degree of organ malfunction and tissue damage brought on by infection, it does not necessarily have an impact on pathogen load, resistant hosts combat infection by inducing an immune response that lowers the pathogen load.”
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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 authors add, “These results open novel therapeutic options by targeting mitochondria and mitohormesis to combat inflammatory challenges and infections.”
