The integrated stress response as a key pathway downstream of mitochondrial dysfunction

Mitochondrial function is fundamental to maintaining metabolic homeostasis. Alterations in mitochondrial biogenesis, energy production, and dynamics are behind many metabolic diseases affecting particularly the muscular and nervous systems. Therefore, synchronized coordination between organelles is required to sustain homeostasis. The integrated stress response (ISR) is a heavily investigated pathway that allows for communication between organelles, including the mitochondria and the nucleus among others. The ISR slows down protein synthesis in the cytoplasm and modifies the transcriptome in the nucleus following mitochondrial stress. With the help of the ATF4 transcription factor, it promotes metabolic rewiring, amino acid, and antioxidant synthesis to counteract cellular stress. Under chronic stress, the ISR leads to apoptotic cell death. However, the mechanisms as to how the ISR can coordinate cell death and survival depending on the type of insult remain unclear. In this review, we will discuss the mechanisms of activation of the ISR under different mitochondrial dysfunctions. We propose a few mechanisms and factors that contribute to the cell-specific response. Finally, we discuss the role of the ISR in neurodegenerative diseases given the important implications of the mitochondria in maintaining healthy neurological function.