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

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 (UPR(mt)), are being examined. UPR(mt) englobes several compensation processes related to proteostasis and antioxidant mechanisms. UPR(mt) 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 UPR(mt) 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 UPR(mt) activation therapeutic strategies, UPR(mt)’s role in diseases, and its possible negative consequences in particular pathological conditions.