Cytosolic Proteostasis Networks of the Mitochondrial Stress Response

Cytosolic proteostatic networks activated during mitochondrial stress involve the regulation of protein synthesis, folding, and degradation, and act in parallel to nucleus-dependent mechanisms. Cap-dependent protein synthesis is inhibited upon mitochondrial stress, while cap-independent translation mechanisms are activated to synthesize stress-associated proteins. The activity of the proteasome is induced during stress by the accumulation of mitochondrial precursors, but is inhibited by electron transport chain dysfunction leading to oxidative stress. Reduced mtHSP70 expression or alteration of lipid metabolism can simultaneously activate the mitochondrial unfolded protein response and the heat shock response to restore mitochondrial and cytosolic proteostasis. Positive regulators of protein synthesis are induced in mitochondrial diseases, and inhibiting translation ameliorates the pathological phenotype by reducing energy consumption and proteotoxicity. Mitochondrial stress requires timely intervention to prevent mitochondrial and cellular dysfunction. Re-establishing the correct protein homeostasis is crucial for coping with mitochondrial stress and maintaining cellular homeostasis. The best-characterized adaptive pathways for mitochondrial stress involve a signal originating from stressed mitochondria that triggers a nuclear response. However, recent findings have shown that mitochondrial stress also affects a complex network of protein homeostasis pathways in the cytosol. We review how mitochondrial dysregulation affects cytosolic proteostasis by regulating the quantity and quality of protein synthesis, protein stability, and protein degradation, leading to an integrated regulation of cellular metabolism and proliferation. This mitochondria to cytosol network extends the current model of the mitochondrial stress response, with potential applications in the treatment of mitochondrial disease. Mitochondrial stress requires timely intervention to prevent mitochondrial and cellular dysfunction. Re-establishing the correct protein homeostasis is crucial for coping with mitochondrial stress and maintaining cellular homeostasis. The best-characterized adaptive pathways for mitochondrial stress involve a signal originating from stressed mitochondria that triggers a nuclear response. However, recent findings have shown that mitochondrial stress also affects a complex network of protein homeostasis pathways in the cytosol. We review how mitochondrial dysregulation affects cytosolic proteostasis by regulating the quantity and quality of protein synthesis, protein stability, and protein degradation, leading to an integrated regulation of cellular metabolism and proliferation. This mitochondria to cytosol network extends the current model of the mitochondrial stress response, with potential applications in the treatment of mitochondrial disease. a mitochondrial protein catalyzing ADP versus ATP exchange across the inner mitochondrial membrane. It is necessary to transport ATP molecules from mitochondria to the cytosol. a multifactorial neurodegenerative disease characterized by the progressive accumulation of amyloid-β (Aβ) plaques in cerebral cortex and hippocampus, and by mitochondrial dysfunction in the affected tissues. It is the leading cause of dementia worldwide. an inhibitor of protein synthesis. It blocks translation elongation by binding to the ribosome and inhibiting eEF2-mediated translocation of peptidyl tRNAs. a multiprotein complex embedded in the inner mitochondrial membrane that has a key role in the final stage of aerobic respiration in the mitochondria leading to the generation of ATP. It consists of complex I (NADH-coenzyme Q oxidoreductase), complex II (succinate-Q oxidoreductase), complex III (Q-cytochrome c oxidoreductase), complex IV (cytochrome c oxidase), and the ATP synthase. cellular repair response activated by proteotoxic stress of the ER (UPRER). The UPRER aims at restoring homeostasis by decreasing protein translation, degrading misfolded proteins, and inducing molecular chaperones involved in protein folding. Prolonged activation of the UPRer can also lead to apoptosis. a kidney disease in humans and mouse models that leads to sclerosis of some but not all glomeruli. In mice, this is a major renal complication as a consequence of mitochondrial DNA deletion and mutation in mitochondrial genes such as tRNAsLeu, tRNAsIle, tRNAsPhe, and the complex I subunit MTND5. a predominantly cytosolic stress response to heat shock and other stress stimuli that results in the transcriptional upregulation of genes encoding heat shock proteins (HSPs) to restore cellular proteostasis. HSPs are typically chaperones which ensure the correct folding of nascent and misfolded proteins. a mitochondrial disease, also known as subacute necrotizing encephalomyelopathy (SNEM), with onset usually in infancy or childhood. It is a rare (one in 40 000 births) disease characterized by progressive neurodegeneration. Leigh syndrome is caused by several mutations in genes coding for respiratory chain enzymes and oxidative phosphorylation assembly factors such as SURF1. The most common mutation occurs in the mitochondrial MT-ATP6 gene which encodes a subunit of complex V. a protein synthesis mechanism that is mediated by recruitment of the translation machinery to mRNA 5′-UTR sequences containing m6A which allow cap-independent translation of the transcript. also known as mitochondrial autophagy, a process that mediates the elimination of damaged or dysfunctional mitochondria and controls mitochondrial number. Mitophagy is controlled in different cell types and tissues by different effectors and receptors, and it operates through ubiquitin-dependent and ubiquitin-independent pathways. The best-characterized ubiquitin-dependent mechanism for clearance of dysfunctional mitochondria is the PINK1–Parkin axis. Additional effectors of ubiquitin-dependent mitophagy include the E3 ligases March5 and Mul1. Ubiquitin-independent pathways instead occur via the mitophagy receptors BNIP3 (BCL2/adenovirus E1B 19 kDa protein interacting protein 3), NIX (NIP3-like protein X)/BNIP3L, and FUNDC1 (FUN14 domain-containing 1). a conserved serine/threonine kinase. mTOR complex I (mTORC1) is composed of mTOR, the catalytic subunit of the complex, and the regulatory proteins Raptor, mLST8, PRAS40, and Deptor. mTORC1 is the most widely studied complex and is a crucial regulator of cap-dependent protein synthesis, as well as of other biological process involved in cell metabolism and proliferation such as cell-cycle regulation, apoptosis, and autophagy. an inhibitor of the Ser/Thr protein kinase mTOR. It specifically blocks mTOR phosphorylation of downstream effectors such as S6K and 4EBP. broad-spectrum antibiotics that inhibit bacterial protein synthesis by inhibiting the interaction of aminoacyl-tRNAs with the mRNA–ribosome complex through binding to the 30S ribosomal subunit in the mRNA translation complex. They also inhibit the translation of proteins encoded by mitochondrial DNA, but not by nuclear DNA, in eukaryotic cells.