Cytosolic Proteostasis Networks of the Mitochondrial Stress Response

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. 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.