JCB_201702058 2027..2046

Mitochondria are key for energy metabolism within the cell, as they produce most of the cellular ATP through oxidative phosphorylation (OXP HOS) and are essential for regulating intermediate metabolism (Nunnari and Suomalainen, 2012). Changes in mitochondrial function impact not only cellular metabolism but also whole-body metabolism, thus affecting healthspan and lifespan. Nearly 300 human diseases are caused by mutations or defects in mitochondrial proteins, half of which are consequence of defects in OXP HOS, for which treatment options remain scarce (Koopman et al., 2012). Additionally, a decline in mitochondrial function is also at the basis of many other common disorders, including diseases that affect the metabolic, muscular, neurological, and immune systems (Andreux et al., 2013), that are often linked with aging (Houtkooper et al., 2010; López-Otín et al., 2013, 2016). Mitochondrial function is also affected in cancer. However, unlike in other diseases, here they are not at the origin of tumorigenesis; cancer cells modify cellular metabolism and mitochondrial function for their own purposes, using them as anabolic machines (Zong et al., 2016). Understanding how mitochondria respond to stress and how mitonuclear communication pathways adapt cellular metabolism to environmental changes is thus not only critical from a basic point of view but also has great translational value given the link between mitochondria and a variety of diseases. Mitochondria are signaling organelles that continuously communicate with the nucleus (Chandel, 2015; Quirós et al., 2016; Matilainen et al., 2017). This coordination is extremely important for energy harvesting, because OXP HOS complex components are encoded in both nuclear and mitochondrial genome, and their expression needs to be tightly regulated to ensure proper assembly and function (Couvillion et al., 2016). Although mitochondria contain an intricate and intrinsic mitochondrial protein quality control system, mainly mediated by proteases (Quirós et al., 2015), upon mitochondrial stress, mitonuclear signals also instruct the nucleus to activate an adaptive response. Mitochondrial stress stimulates the synthesis of Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans–expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals