Respiratory complex I deficiency triggers OMA1-mediated integrated stress response and affects lipid homeostasis during glucose restriction

Severe impairment of respiratory complex I (CI) has been demonstrated to slow down tumor progression, thus prompting preclinical studies on the use of its inhibitors in different types of cancers. However, we demonstrated that cancer cells lacking CI are able to activate adaptive responses that support survival despite the energetic deficit, thus allowing the subsequent tumor repopulation. Since such mechanisms are far from being understood, we generated and exploited multiple cancer cells of different origin lacking CI (CInull) to elucidate their response to energetic stress. Upon glucose restriction, CInull cells showed significant mitochondrial network fragmentation and depolarization due to activation of OMA1, as shown by OPA1 and PGAM5 cleavage and DRP1 dephosphorylation. These mitochondrial alterations were accompanied by a consistent activation of Integrated Stress Response (ISR), which is orchestrated by OMA1 and suppressed when the protease expression is downregulated. Similar results were obtained by specific CI pharmacological inhibition with EVP-4593. Moreover, we found that glucose starvation triggered the accumulation of lipid droplets (LDs) in contact with deranged mitochondria in vitro and in vivo, accompanied by a profound remodelling of lipid content, in particular of triacylglycerols and in cholesteryl esters. However, inhibition of LDs biogenesis did not affect cell viability, suggesting that they are not implicated in cell survival upon glucose restriction. On the other hand, OMA1 silencing and the consequent block of ISR in CInull cells trigger cell death, indicating that mechanism is necessary to support cell survival. Overall, this study revealed that CI dysfunction, glucose restriction and ISR are in synthetic lethality, thus pointing to a combined metabolic approach to eradicate tumors.