Fig. 1

Mitochondrial stress response pathways. Environmental disturbance or impairment result in a decrease in mitochondrial stressor (ROS, mtDNA, ETC inhibition and PAMPs/DAPMs). Mitochondrial stress is activated to respond those stressors. A The mutant form of Ant1/Aac2 impairs the structural stability of TIM22, which in turn inhibits the biogenesis of TIM23 and induces instability in the IMM. This disruption results in proteostasis stress and triggers mitochondrial precursor overaccumulation stress (mPOS). B The unfolded protein response in mitochondria (UPRmt) is regulated by competing organelle targeting sequences within the transcription factor ATFS-1. When ATFS-1 is imported into the mitochondrial matrix via the MTS, it is subjected to degradation. However, in cases of mitochondrial dysfunction where ATFS-1 cannot be imported, it is redirected to the nucleus through the nuclear localization sequence (NLS). There, it activates the transcription of mitochondrial chaperones and proteases. C Under normal conditions, mitochondrial protein import undergoes rigorous monitoring by various quality control mechanisms, including ribosomal quality control (RQC) and mitochondrial translocation-associated degradation (mitoTAD). However, if RQC and mitoTAD are impaired due to mitochondrial dysfunction, a response known as mitochondrial compromised protein import response (mitoCPR) occurs within the cells. D Mitochondria transmit stress signals, activating the integrated stress response (ISR). This classic pathway involves four stress-activated kinases: PKR, PERK, GCN2, and HRI. They phosphorylate eIF2α during cellular stress, inhibiting protein biosynthesis and activating ATP4 transcription, thus promoting adaptive and apoptotic gene expression in response to stress. E Recognition and selective degradation of damaged mitochondria is mediated by mitophagy. The kinase PINK1 is stabilized specifically on damaged mitochondria where it recruits the ubiquitin ligase Parkin, which ubiquitinates multiple mitochondrial outer membrane proteins. Ubiquitinated mitochondria are then engulfed by autophagosomes and trafficked to lysosomes where they are degraded