Updated project metadata. Mitonuclear communication is essential to maintain cellular and organismal homeostasis in equilibrium and stress. Mitochondrial stress activates a concerted mitonuclear response geared to safeguard and repair mitochondrial function and to adapt cellular metabolism to the stress. However, the common mediator driving this stress response in mammals remains elusive. By using a multi-omics approach we identify that the activating transcription factor 4 (ATF4) is the main player regulating this response. ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism, through activation of the integrated stress response (ISR). Mitochondrial stress also promotes a local proteostatic response, by inducing a decrease in mitochondrial ribosomal proteins, inhibiting mitochondrial translation and coupling as such the activation of the ISR with the attenuation of mitochondrial function. Our data illustrate the value of a multi-omics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.