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

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.

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

“…Activation of mtUPR has been proposed as a therapeutic target in several diseases [15,78,79], encompassing neurodegenerative [80][81][82][83][84][85][86], cardiovascular [87][88][89][90][91], metabolic [92][93][94], cancer [95][96][97][98][99][100][101][102][103][104][105][106], and mitochondrial diseases [8,14]. Taking advantage of this and the screening system based on cell culture in galactose medium, we tested different activators of mtUPR.…”

Mitochondrial Stress and Mitokines: Therapeutic Perspectives for the Treatment of Metabolic Diseases

“…GDF15 expression is related to the UPR mt and ISR [ 125 , 126 ]. When mitochondrial stress occurs, the UPR mt activates transcription of GDF15, which in turn is modulated by the ISR.…”

“…The precise molecular mechanisms by which the ISR and UPR mt integrate to express GDF15 are not fully understood. UPR mt activation leads to the upregulation of various nuclear-encoded mitochondrial chaperones and proteases, which help to maintain mitochondrial proteostasis [ 125 ]. On the other hand, the ISR is activated in response to various cellular stress conditions, including endoplasmic reticulum stress, amino acid starvation, and oxidative stress, and aims to restore cellular homeostasis by modulating protein synthesis, folding, and degradation [ 126 ].…”

Neurodegeneration, Mitochondria, and Antibiotics

“…Therefore, preventing the decrease in cAMP signaling and the loss of CREB-regulated gene transcription represents a valid therapeutic strategy for HD [ 217 ]. CREB induces transcription of thousands of target genes, some of which are related to the UPR mt [ 218 , 219 ]. The role of the CREB protein family in the central nervous system has been shown to support neuronal survival [ 220 ], regulate neuronal migration [ 221 ], modulate synaptogenesis [ 222 ], and contribute to the formation of long-term potentiation and memory [ 223 ].…”