Activation of the Mitochondrial Unfolded Protein Response: A New Therapeutic Target?

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Abstract

Mitochondrial dysfunction is a key hub that is common to many diseases. Mitochondria’s role in energy production, calcium homeostasis, and ROS balance makes them essential for cell survival and fitness. However, there are no effective treatments for most mitochondrial and related diseases to this day. Therefore, new therapeutic approaches, such as activation of the mitochondrial unfolded protein response (UPRmt), are being examined. UPRmt englobes several compensation processes related to proteostasis and antioxidant mechanisms. UPRmt activation, through an hormetic response, promotes cell homeostasis and improves lifespan and disease conditions in biological models of neurodegenerative diseases, cardiopathies, and mitochondrial diseases. Although UPRmt activation is a promising therapeutic option for many conditions, its overactivation could lead to non-desired side effects, such as increased heteroplasmy of mitochondrial DNA mutations or cancer progression in oncologic patients. In this review, we present the most recent UPRmt activation therapeutic strategies, UPRmt’s role in diseases, and its possible negative consequences in particular pathological conditions.

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The integrated stress response.

Karolina Pakos-Zebrucka, Izabela Koryga, Katarzyna Mnich … (2016)

In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli. Although the ISR is primarily a pro-survival, homeostatic program, exposure to severe stress can drive signaling toward cell death. Here, we review current understanding of the ISR signaling and how it regulates cell fate under diverse types of stress.

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2020 Alzheimer's disease facts and figures

(2020)

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Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance.

Sarah Pickles, Pierre Vigié, Richard Youle (2018)

The maintenance of a healthy and functional mitochondrial network is critical during development as well as throughout life in the response to physiological adaptations and stress conditions. Owing to their role in energy production, mitochondria are exposed to high levels of reactive oxygen species, making them particularly vulnerable to mitochondrial DNA mutations and protein misfolding. Given that mitochondria are formed from proteins encoded by both nuclear and mitochondrial genomes, an additional layer of complexity is inherent in the coordination of protein synthesis and the mitochondrial import of nuclear-encoded proteins. For these reasons, mitochondria have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria are present to meet the demands of the cell. These pathways work to eliminate damaged mitochondrial proteins or parts of the mitochondrial network by mitophagy and renew components by adding protein and lipids through biogenesis, collectively resulting in mitochondrial turnover. Mitochondrial quality control mechanisms are multi-tiered, operating at the protein, organelle and cell levels. Herein, we discuss mitophagy in different physiological contexts and then relate it to other quality control pathways, including the unfolded protein response, shedding of vesicles, proteolysis, and degradation by the ubiquitin-proteasome system. Understanding how these pathways contribute to the maintenance of mitochondrial homeostasis could provide insights into the development of targeted treatments when these systems fail in disease.