mtUPR Modulation as a Therapeutic Target for Primary and Secondary Mitochondrial Diseases

Mitochondrial dysfunction is a key pathological event in many diseases. Its role in energy production, calcium homeostasis, apoptosis regulation, and reactive oxygen species (ROS) balance render mitochondria essential for cell survival and fitness. However, there are no effective treatments for most primary and secondary mitochondrial diseases to this day. Therefore, new therapeutic approaches, such as the modulation of the mitochondrial unfolded protein response (mtUPR), are being explored. mtUPRs englobe several compensatory processes related to proteostasis and antioxidant system mechanisms. mtUPR activation, through an overcompensation for mild intracellular stress, promotes cell homeostasis and improves lifespan and disease alterations in biological models of mitochondrial dysfunction in age-related diseases, cardiopathies, metabolic disorders, and primary mitochondrial diseases. Although mtUPR activation is a promising therapeutic option for many pathological conditions, its activation could promote tumor progression in cancer patients, and its overactivation could lead to non-desired side effects, such as the increased heteroplasmy of mitochondrial DNA mutations. In this review, we present the most recent data about mtUPR modulation as a therapeutic approach, its role in diseases, and its potential negative consequences in specific pathological situations.

Automated summary

Mitochondrial dysfunction plays a crucial role in various diseases, but effective treatments for mitochondrial diseases are still lacking. Therefore, researchers are exploring new therapeutic approaches, such as modulating the mitochondrial unfolded protein response (mtUPR). Activation of mtUPR can promote cell homeostasis and improve lifespan and disease conditions in biological models of mitochondrial dysfunction. However, mtUPR activation may also promote tumor progression and lead to undesirable side effects, such as increased heteroplasmy of mitochondrial DNA mutations.