Trends in Biochemical Sciences
ReviewCytosolic Proteostasis Networks of the Mitochondrial Stress Response
Section snippets
Mitochondrial Dysfunction and Stress Responses
Mitochondria have key functions within the cell, providing energy and essential metabolic intermediates to ensure cellular homeostasis [1]. As such, at an organismal level mitochondria contribute to complex physiological processes in health, and when their function is perturbed they contribute to the development of many diseases and aging [2]. Mitochondrial function relies both on the nucleus, which encodes the majority of mitochondrial proteins, and the mitochondrial genome, which encodes 13
Shutting Down Protein Translation
A common response of cells to stress is to decrease proliferative and metabolic activity and to shut off energy-demanding biological processes. This allows cells to reduce the propagation of the stress-induced damage and to spare energy to mount an efficient response. Acting at the protein level allows a faster response than regulating transcriptional programs. Indeed, protein translation is the most energy-expensive process in the cell [15] and can be quickly and efficiently modulated [16],
Mitochondrial Stress Responses: Toward a Unifying Model?
Cellular stress response pathways were initially discovered and described as compartment-specific adaptations to different types of stressors, such as the UPRER in the ER, the UPRmt occurring within the mitochondria, and the HSR in the cytosol (Box 1, Box 2). However, recent screenings and omics analyses have extended the number and definitions of cellular and organismal signatures of the mitochondrial stress response. It is now evident that perturbation of the mitochondrial compartment results
Cytosolic Proteostasis in the Mitochondrial Stress Response: Pharmacological Implications
Proteotoxicity is a major contributor to the pathogenesis of several mitochondrial diseases, and restoring proteostasis by targeting protein translation or the UPS is emerging as a promising therapeutic strategy. Reducing protein translation by inhibiting the mTOR pathway can successfully rescue mitochondrial disease phenotypes. Mouse models of Leigh syndrome treated with the mTOR inhibitor rapamycin showed increased survival and reduced disease features 32, 74. In FSGS mice models, rapamycin
Concluding Remarks
Mitochondrial stressors encompass a large variety of insults which disrupt mitochondrial function though different mechanisms. Nonetheless, some common responses to these stimuli have emerged. Together with the well-known mitonuclear response, which acts mainly through transcription factors such as ATFS-1 in C. elegans [85] and ATF4 in mammals, 38, 39, several studies have recently unveiled an array of cytosolic response pathways including mPOS, UPRam, and MCSR. These responses aim at restoring
Acknowledgments
D.D. is supported by a fellowship funded by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and the Marie Skłodowska-Curie Actions. V.S. is supported by the ‘EPFL Fellows’ program co-funded by Marie Skłodowska-Curie Actions and Horizon 2020 (grant agreement 665667). J.A. is supported by the EPFL, the Swiss National Science Foundation (310030B_160318), the AgingX program of the Swiss Initiative for Systems Biology (51RTP0-151019), and the National Institutes of Health (R01AG043930).
Glossary
- ATP/ADP translocase
- 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.
- Alzheimer’s disease (AD)
- 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.
- Cycloheximide
- an inhibitor
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Equal contribution.