How the Mitoprotein-Induced Stress Response Safeguards the Cytosol: A Unified View

Owing to their post-translational mode of import, mitochondrial precursor proteins represent a significant challenge to the cells’ ability to maintain cytosolic proteostasis, particularly when the amount of cytosolic precursors exceeds the import capacity of mitochondria. Mitoprotein-induced stress elicits a complex regulatory network that: (i) removes stalled precursors from the mitochondrial surface, (ii) slows down the synthesis of mitochondrial proteins, and (iii) increases the levels of chaperones and proteases and attenuates cytosolic translation. Seemingly disparate reactions to mitochondrial stress are integrated into a general mitoprotein-induced stress response that couples ‘mitochondria-centric’ adaptations with general stress programs such as the heat shock response. Mitochondrial and cytosolic proteostasis are of central relevance for cellular stress resistance and organismal health. Recently, a number of individual cellular programs were described that counter the fatal consequences of mitochondrial dysfunction. These programs remove arrested import intermediates from mitochondrial protein translocases, stabilize protein homeostasis within mitochondria, and, in particular, increase the levels and activity of chaperones and the proteasome system in the cytosol. Here, we describe the different responses to mitochondrial perturbation and propose to unify the seemingly distinct mitochondrial-cytosolic quality control mechanisms into a single network, the mitoprotein-induced stress response. This holistic view places mitochondrial biogenesis at a central position of the cellular proteostasis network, emphasizing the importance of mitochondrial protein import processes for development, reproduction, and ageing. Mitochondrial and cytosolic proteostasis are of central relevance for cellular stress resistance and organismal health. Recently, a number of individual cellular programs were described that counter the fatal consequences of mitochondrial dysfunction. These programs remove arrested import intermediates from mitochondrial protein translocases, stabilize protein homeostasis within mitochondria, and, in particular, increase the levels and activity of chaperones and the proteasome system in the cytosol. Here, we describe the different responses to mitochondrial perturbation and propose to unify the seemingly distinct mitochondrial-cytosolic quality control mechanisms into a single network, the mitoprotein-induced stress response. This holistic view places mitochondrial biogenesis at a central position of the cellular proteostasis network, emphasizing the importance of mitochondrial protein import processes for development, reproduction, and ageing. mediates the removal of proteins from the ER lumen or membrane by proteasomal degradation. signaling pathway that is induced by the accumulation of unfolded or misfolded proteins in the cytosol and/or nucleus. The HSR is triggered by exposure to high temperature but can be induced by any conditions that promote protein misfolding. extraction system to remove arrested import intermediates from the TOM complex. Cis1 (together with Tom70) recruits the AAA extractor Msp1 to the TOM complex for back-translocation of precursors into the cytosol. describes the toxic accumulation of mitochondrial inner membrane proteins in the cytosol of yeast cells. degradation system to remove stalled translation intermediates from the TOM complex. For protein degradation of precursor proteins, the bridging factor Ubx2 recruits Cdc48 and the proteasome to the outer membrane receptor Tom70. (mitochondrial ribosome quality control); mutated mRNAs can irreversibly arrest translating ribosomes. If these stalled translation intermediates are targeted to mitochondria, a dedicated machinery recognizes and dissociates them to release the ribosome and degrade the nonproductive nascent polypeptides. (presequence) at the N terminus of mitochondrial precursor proteins. In most cases, presequences are removed after the import reaction by the mitochondrial processing peptidase giving rise to a mature mitochondrial protein. signaling pathway that is induced by the accumulation of unfolded or misfolded proteins in the mitochondrial matrix. highly reactive molecules, including superoxide, hydrogen peroxide, and hydroxyl radicals, that are formed by electron transfer to oxygen. Are produced as byproducts by the mitochondrial respiratory chain. the central pore-forming subunit Tom40 serves as general entry gate for mitochondrial precursor proteins. Receptors such as Tom70 and Tom20/22 recognize cytosolic precursors and direct them to Tom40. signaling pathway that is induced by mitochondrial precursor proteins, which accumulate in the cytosol. signaling pathway that is induced by the accumulation of unfolded or misfolded proteins in the lumen or the membrane of the endoplasmic reticulum (ER).