DELE1 is a mitochondrial stress sensor that relays dysfunction to the cytosol through a proteolytic signaling cascade. Upon mitochondrial stress, the mitochondrial protease OMA1 cleaves DELE1 from the inner mitochondrial membrane, releasing a C-terminal fragment that accumulates in the cytosol 12. This cytosolic DELE1 fragment specifically binds to and activates the protein kinase HRI (EIF2AK1), triggering the integrated stress response (ISR) through eIF2α phosphorylation 12. This phosphorylation suppresses global protein synthesis while selectively inducing ATF4, a master transcriptional regulator of stress adaptation 123. DELE1 oligomerizes into high-order octameric complexes that enhance HRI activation efficiency 4. Beyond canonical stress, DELE1 detects perturbations in mitochondrial protein import and processing, responding to defects at the TIM/TOM complex and matrix proteolysis 5. Recent evidence indicates DELE1-HRI activation also promotes PRKN-independent mitophagy by localizing eIF2α phosphorylation to mitochondria 6. Notably, DELE1-HRI acts as a negative regulator of PINK1-dependent mitophagy 7, revealing complex crosstalk between mitochondrial quality control pathways. These mechanisms position DELE1 as a critical hub integrating diverse mitochondrial stresses for appropriate cellular response.