Mitochondria are essential organelles participating in numerous cellular functions, including energy harvesting, regulation of homeostasis and apoptosis. Changes in mitochondrial number, morphology, and function not only impact cellular metabolism but also critically influence whole-body metabolism, health, and lifespan. Mitochondrial dysfunction is strongly associated with age-associated conditions such as neurodegenerative disorders, cardiovascular diseases, metabolic diseases, and sarcopenia. Given this, mitochondrial-targeted therapies represent promising treatment options for these conditions and are being extensively studied. One of these new approaches is the pharmacological induction of mitochondrial stress responses (MSR) which include mitophagy and the mitochondrial unfolded protein response (UPRmt). The UPRmt is a proteotoxic stress response that senses protein-folding perturbations exceeding the capacity of the mitochondrial quality control network. The UPRmt activates the expression of nuclear-encoded quality control proteins along with other protective genes to re-establish mitochondrial homeostasis.

In the present study, we screened a library of 770 FDA-approved compounds in the nematode Caenorhabditis elegans to uncover novel MSR inducers. From this screen, we identified two potent mitochondrial stressors that notably improved the lifespan and healthspan of treated animals. Further analysis of the compounds effect in the nematode revealed the implication of various cellular stress responses including the heat shock stress response, the hypoxia stress response, the mitochondrial stress response, and the insulin/IGF-1 signaling (IIS) pathway mediated by FOXO/daf-16. Further validation in HEK293T cells confirmed their efficacy as mitochondrial stressors and suggested a conservation of the mechanism, highlighting their potential relevance for treating mitochondrial diseases.