Fig. 2

Mitochondrial dysfunction and ISR: The activation of the integrated stress response (ISR) during mitochondrial dysfunction is triggered by various mechanisms. The fragmentation of mitochondrial DNA is among the leading causes of mitochondrial dysfunction, which is managed by an ISR sensor, protein kinase RNA-activated (PKR). Mitochondrial dysfunction during amino acid metabolism is managed by another class of ISR kinase- general control nonderepressible-2 (GCN2). The Tri-Carboxylic Acid (TCA) cycle is fed via the amino acid degradation during metabolic rewiring stage of mitochondrial stress, and the depletion of amino acids results in activation of GCN2. During this process, the equilibrium maintenance of reducing equivalents is maintained by the malate and aspartate shuttle. Upon induction of mitochondrial stress by generation of reactive oxygen species (ROS), a mitochondrial protease known as OMA1 regulates the mitochondrial stress dynamics by cleaving DAP3-binding cell death enhancer 1 (DELE1). This subsequently activates heme-regulated inhibitor (HRI) after translocating to the cytoplasm. The crosstalk between mitochondria and endoplasmic reticulum aids ER to sense the alterations in the levels of calcium (Ca2 +), ROS, and changes in energy productions; leading to activation of ER transmembrane protein- PKR-like ER kinase (PERK). Upon mitochondrial dysfunction and the ER-mitochondrial crosstalk, these protein kinases phosphorylate eIF2α and inhibit global protein translation to mitigate stress and restore the normal homeostasis. Until the stress is resolved, a translational shift due to upstream open reading frame (uORF) mediates selective translation of proteins such as ATF-4 and usurps the global translation to mitigate the stress. ATF-4 along with its other dimerization partners regulates amino acid synthesis genes, antioxidant pathways, chaperones and metabolism related genes to restore the homeostasis post stress. However, chronic stress results in activation of CHOP-mediated apoptotic cell death. Figure was created in BioRender